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Past Issues
Volume 17, number 7/8
July/August 2003
Individual Access Universal
Barriers
Familiar problems and promise come with access to HIV care
Concrete Results
Abstracts on ART in Sub-Saharan Africa
Baby Steps
MSF pilot programs show what is possible
HCV Around the World
HCV prevention and treatment in a global context
India Song
Maitreya looks at why prevention programs are failing
Drug News
Mysterious interactions, guidelines and new approvals
South Africa Relents
HIV drugs may finally be getting government support
The Spectrum of Access
By Bob Huff
The accessibility of quality HIV care, with and without antiretroviral
therapy (ART), varies widely across the globe. As drug prices have
fallen in resource-poor areas, dozens of small pilot programs are
now proving that that therapy is effective, feasible and subject
to problems familiar in the rich countries. Meanwhile, in the U.S.,
several hundred thousand people are estimated to have HIV and not
know it or want to deal with it. Many of these people have limited
access to care and may finally enter the system only after symptoms
develop. Barriers to care, such as stigma, lack of knowledge, and
lack of money, cut across hemispheres and time zones.
At the International AIDS Society’s 2nd IAS Conference
on Pathogenesis and Treatment, held in Paris this summer, 17
abstracts reported on the experience of treating over 2,400 patients
with ARV in 11 countries in Sub-Saharan Africa. Additional reports
of successful treatment programs in Latin America and Asia peppered
the conference abstract book. This is up from the handful of papers
presented at 2002’s much larger International AIDS Conference
in Barcelona. Clearly a lot has been accomplished in the intervening
12 months, but of the estimated 300,000 people receiving ART in
the developing world, half are in Brazil and fewer than 30,000 are
thought to be on treatment in Africa. With at least 4 million people
in need of treatment in that region alone, the often-stated goal
of treating 3 million worldwide by 2005 seems to be slipping out
of reach.
Not so, says Paulo Teixeira, the architect of Brazil’s successful
ART program who has just taken over as the new chief of HIV/AIDS
at the World Health Organization (WHO), the body that set the target
at 3 million. “My belief is that it is absolutely feasible,
despite the magnitude of the task,” Teixeira told Reuters.
The daunting reality is that achieving WHO’s goal means treating
100,000 new people every month from now until the end of 2005. Yet,
despite the slow pace to date, there are signs that treatment programs
are poised to accelerate as costs decline and funding increases.
Here are a few selected reports from the Paris conference that sketch
the outlines of what is possible and where problems persist.
Generally, the reports of pilot treatment programs tell stories
of improved CD4 counts, fewer deaths and fair adherence. At the
2002 International AIDS Conference in Barcelona, the Heineken brewing
company reported that providing ART to employees and spouses was
affordable, if not strictly justified on a cost/benefit basis. A
year later the company has presented an analysis of changing costs
in AIDS-associated medical expenses, absenteeism and death after
the institution of their treatment program at a brewery in Burundi.
They now find that the benefits do justify the costs.
Thirty-one persons have started treatment since the Heineken program
began in September 2001. Hospitalization for opportunistic infections
declined from an average of 20 per year (1997-2000) to 10 in 2001
to only 6 in 2002; deaths declined from 11 to 2 to 1 during the
same periods. Time off due to illness also declined. Meanwhile,
voluntary HIV testing increased from an average of 13 per year (1997-2000)
to 123 in 2001 and 140 in 2002. Overall costs were 58,188 euros
($66,000), including 47,207 for drugs, 7,927 for travel and training,
and 3,154 for diagnostic tests. Overall, medical expenses increased
by only 5,233 euros between 2001 and 2002, suggesting that the costs
of treatment were almost entirely recovered by savings in hospitalizations
and other losses. (Gahimbaza)
But government involvement will be essential if treatment programs
hope to reach the huge numbers of people without jobs or family
income. In Cameroon, with nearly 1 million infected, the government
is now providing ART for 7,000 people. Médecins Sans Frontières
(MSF), the international medical organization, reported on a collaborative
pilot project in a military hospital in Yaounde that has treated
117 people since 2001. With effective therapy and good monitoring,
and despite advanced disease in many patients, the authors observed
outcomes comparable to those obtained in rich countries. (A complete
listing of worldwide MSF ART programs is on page 7). (Mougnutou)
A researcher at a care center in Mumbai, India reported on the
struggle to provide antiretroviral drugs to people who need them
when few can afford them. Simply following the “Hit Early,
Hit Hard” paradigm, he says, would result in bankruptcy. To
accommodate the reality of limited resources, the author studied
ways to modify treatment protocols, dosages, combinations and follow-up
to increase affordability, adherence and survival. During the period
from 1995 to 2002, 4100 people with HIV/AIDS were managed by the
clinic, and although 943 were eligible to receive ART by local standards,
only 570 could afford generic drugs. Most who began drug therapy
took an NNRTI and two NRTIs; the rest were given supportive therapy
and treatment for symptoms and opportunistic infections (OI). “CD4
count, clinical status, incidence of OI were studied, but viral
load was dispensed with.” Further cost-saving measures included
extending the follow-up interval by an average of 3.7 months and
reducing dosages by 25–50 percent according to body weight.
The author observed no difference in outcomes between patients treated
on this austerity plan (about $30 per month) and those who received
a PI-based regimen. In this clinic, lowered drug prices, reduced
follow-up costs and simplified patient care protocols resulted in
improved access to ARV. (Gilada)
While costs may be managed, and affordable ART delivered where
there are institutional or corporate resources, the situation when
individuals are on their own is not as bright. One study looked
at the economic status of those who able to receive ART in Cote
d’Ivoire. Not surprisingly, higher personal income was associated
with greater access to treatment. Physicians conducted interviews
with 173 patients receiving ART in five outpatient clinics in Abidjan
during a four-day period in November 2002. The patients had a median
age of 34 years and had been attending the clinic for a median 9
months; over half were women (59%). Of those surveyed, 23 percent
had no personal income; 37 percent received less than $76 per month;
26 percent received between $77 and $288 per month; and 14 percent
had incomes over $288 per month. Of those with incomes, 61 percent
were employed, while the rest reported receiving an allowance from
relatives. The 31 patients (18%) taking ARV had a significantly
higher monthly income than those not being treated (>$76 monthly:
68% vs. 48%, P=0.05). Only 2 patients received ARV for free. The
rest had to pay for all or part of their medication, with 46 percent
paying up to $45 per month; 41 percent paying between $46 and $107
per month; and 14 percent paying more than $107 per month. Relatives
contributed to ARV costs for 45 percent of those surveyed. (Sauvageot)
But there are barriers to receiving care beyond affordability,
among them lack of empowerment, lack of knowledge, social stigma
and fear of disclosure. HIV-positive women in Lusaka were asked
via questionnaire about how accessible they perceived HIV therapy
to be for them. Seventy-one percent had heard about antiretroviral
therapy but did not know exactly what it was; and 14 percent had
purchased drugs — usually Indian generics — and were
taking them. The expense of medications was the most common reason
given for not buying ARV (85%), with 62 percent saying they would
rather spend the money on household expenses. About a quarter of
the women said they had not disclosed their HIV status to their
partners for fear of being blamed for bringing the disease into
the household. Two-thirds of the women said they were dependent
on their spouses for income and 72 percent said the felt the traditional
role of women in society was a factor in making it difficult of
them to obtain access to treatment. (Shumba)
Provider knowledge may be another barrier to effective care, even
where drugs are available. India is a huge, sprawling country with
many cultural traditions that include a range of practitioners of
different medical systems such as ayurveda, homeopathy, Unani, naturopathy,
and modern Western medicine. With over 4 million HIV-infected persons
in India, many of these doctors are increasingly called upon to
practice HIV medicine. A researcher from a government hospital conducted
a survey among 300 family physicians and 60 consultants from both
high- and low-HIV prevalence regions, concerning their level of
knowledge about providing antiretroviral therapy. About three-quarters
of the participants were modern medical practitioners, 20 percent
ayurvedic physicians and 8 percent homeopaths. In the low-prevalence
states, 99 percent had no knowledge of the parameters for initiating
HIV therapy and 70 percent were unaware of diagnostic tests. Although
70 percent had heard of AZT, there was no knowledge of adverse drug
reactions, patient monitoring or pre-therapy counseling.
In high-prevalence areas the results were somewhat better, though
still abysmal. Although 80 percent of doctors were able to write
the names of two or three drugs, the majority were unaware of parameters
for starting therapy. And although most had heard of the CD4 count
as an HIV test, few understood the significance of CD4 results.
The author notes that physicians in India often prescribe antiretroviral
therapy “to pacify the patients without proper protocol or
scientific basis,” thereby risking the development of drug
resistance. Currently, there is no laboratory in India to detect
or monitor emerging drug resistance. (Deshpande)
And lest we think that drug access disparities only occur in faraway
places, the San Francisco Department of Health reported on the uptake
of a new generation antiretroviral, tenofovir, in a setting where
free treatment is guaranteed to all who need it. Using citywide
surveillance data, the authors conducted a retrospective review
of 6,898 people living with AIDS during the period of 1999 to 2002
and identified 403 (5.8%) people who had ever received tenofovir.
About a quarter of these had received the drug prior to approval,
which suggests participation in a clinical trial or expanded access
program. Those never receiving tenofovir were more likely to be
non-white, injection drug users, homeless and have no insurance.
Individuals from upper-income areas were more likely to have had
access to tenofovir than those from lower-income areas. The authors
concluded that their “findings highlight a disquieting inequity
of the American healthcare system that cannot be corrected simply
by making AIDS treatment affordable or free.” (Chen)
Finally, as a counter example to the situation in India and elsewhere,
one can look to the description of a model, comprehensive primary
care HIV clinic provided by the Community Health Network of Rochester,
NY to grasp what state-of-the-art care can entail. Started over
13 years ago, the federal, state and locally funded clinic serves
about 800 patients with five HIV specialist physicians, six social
workers and two aides, five clinical nurses, a research nurse, a
care coordinator, a dietician, and a treatment adherence counselor.
They also have available a psychiatrist, a therapist, a gynecologist,
an optician and a part-time pharmacist. (Perhaps some of these experts
would volunteer to spend next winter teaching in sunny Lusaka. Contact
the International HIV Clinician’s Exchange Program: www.iceha.org)
Also important to note is the patient-centered approach to care
that the Rochester clinic supports with services such as issue-driven
patient group meetings, a patient care-committee and a patient library.
(Corales)
Access to care depends on many factors ranging from income to empowerment
and from price to patient and provider knowledge. As drugs become
more available, access to information and commitment to equitable
availability are emerging as crucial factors for obtaining good
outcomes from HIV care, wherever it is provided.
References
All abstracts are from The 2nd IAS Conference on HIV Pathogenesis
and Treatment, Paris, France, 13-16 July, 2003 and are published
in Antiviral Therapy, Volume 8, Supplement 1, 2003.
Gahimbaza L. Costs and benefits of the antiretroviral therapy
in the private sector: the experience of Brarudi, Burundi. Abstract
668.
Mougnutou R. Evaluation of a HAART pilot study in Yaounde,
Cameroon: 24 months follow-up. Abstract 686.
Gilada I, Comprehensive cost-efficient model of HIV care from
India most suitable for resource-poor settings. Abstract 639.
Sauvageot D. Access to antiretroviral (ARV) drugs in five outpatient
clinics in Abidjan, Cote d’Ivoire. Abstract 642.
Shumba CD, Kwalombota M, Accessibility of HIV therapy to women
living with HIV/AIDS in Lusaka, Zambia. The 2nd IAS Conference on
HIV Pathogenesis and Treatment, Paris, 2003. Abstract 772
Deshpande A. Is India poised for HAART? Abstract 569.
Chen SY. Disparities in community uptake of tenofovir in San
Francisco, California. Abstract 643.
Corales RB. The comprehensive HIV primary care clinic model:
one stop shop. Abstract 648.
ARV in Sub-Saharan Africa: 17
Reports
By Bob Huff
The descriptions below relate experiences treating adults with
antiretroviral (ARV) medicines in Sub-Saharan Africa and were presented
at the 2nd IAS Conference on Pathogenesis and Treatment, Paris.
Seventeen abstracts described clinical outcomes, adherence, and
costs of treating 2442 adult patients in 10 African countries. In
addition to these, a number of other papers discussed treatment
experiences in Asia and Latin America. Most studies were retrospective
chart reviews; no randomized treatment trials were reported. Numbers
refer to published abstracts; full references at end of article.
Abstract 112 — A treatment program in two hospitals and 10
clinics in the Chiradzulu district, Malawi run by the Ministry of
Health and Médecins Sans Frontières (MSF) reported
on treating 464 adults since August 2001 with an NNRTI-based regimen.
From a baseline of 109, median CD4 cell counts/mm3 increased by
142 at 6 months and by 133 at 12 months. During the period 64 patients
died, 15 were lost to follow-up, 4 were non-compliant and 9 went
off treatment due to toxicity or OI treatment. At time of last visit,
93% reported taking at least 80% of their prescribed therapy.
Abstract 629 — The Nigerian national treatment program reported
on the 12, 24 and 36-week experience of 74 patients receiving generic
nevirapine, lamivudine and stavudine at three centers during March
to December, 2002. Women comprised 35% of the patients. The mean
CD4 cell count/mm3 increased from 214 at baseline to 298 at week
12, and 348 at week 24. Median weight increased from 51.7 kg at
baseline to 55.7 kg at week 12, 63.6 kg at week 24, and 62.7 kg
at week 36. At baseline, 20.8% had TB and one patient died from
TB within one week of starting treatment. The most common adverse
events were peripheral neuropathy and rash. Cost was identified
as a barrier to regular follow-up.
Abstract 636 — The Benin national treatment program conducted
a chart review to assess characteristics of 448 patients who were
receiving ART during a period between December 2001 and February
2003. A PI-containing regimen (indinavir or nelfinavir) was prescribed
for 55% and an NNRTI regimen (efavirenz) for 45%. Women comprised
47% of those reviewed. Most patients were infected with HIV-1 (98.4%)
with 0.6% having HIV-2 and 1% having both. BMI was less than 18.5
for 35%. The most frequent OIs were wasting, 86%; oral candidiasis,
49%; and dermatitis, 46%. TB was reported in 4% of patients. The
delay from diagnosis to treatment was less than 6 months in 56%;
between 6 and 12 months in 14%; from 1 to 2 years in 18% and over
2 years in 12%.
Abstract 668 — A company-sponsored treatment program for
employees of the Heineken brewery in Braudi, Burundi reported the
costs and benefits after 18 months experience treating 31 persons.
Hospitalizations declined from an average of 20 per year prior to
ART to 10 in 2001 and 6 in 2002. Deaths declined from 11 prior to
ART to 2 in 2001 to 1 in 2002. Program costs were almost completely
recovered by savings in medical care.
Abstract 686 — A treatment project at a military hospital
in Yaounde, Cameroon reported on the 24-month experience of a pilot
program treating 117 persons with a nevirapine-based regimen. Nelfinavir
was substituted in 5 cases and efavirenz in 4 cases. The median
length of follow-up was 10.5 months. Women comprised 69% of the
patients. The median CD4 cell count/mm3 increased from 151 at baseline
to 250 at 12 months. Viral load became undetectable in 85.2% of
cases. The median BMI increased from 23.2 to 25.2. Eleven patients
changed treatment due to adverse events and 1 due to nevirapine
resistance. Nine patients died, with a median time to death of 9
months.
Abstract 690 — A clinical research center in Kampala, Uganda
assessed adherence in 28 persons starting treatment with Triomune
(generic NVP/3TC/D4T) using multiple techniques including self-report,
visual analog scale (VAS), MEMS and unannounced pill counts. Patients
were followed for 1 to 6 months (mean 3.1). Results from the various
techniques were well correlated with each other; mean adherence
ranged from 87% to 91%.
Abstract 693 — A clinical research center in Kampala, Uganda
reported on therapeutic responses to a regimen containing efavirenz,
zidovudine and lamivudine in 11 patients with non-B subtype HIV-1
(A, D), many with baseline viral loads above 100,000 copies/mL.
At 12 weeks, 89% were below detectable levels of HIV RNA; at 31
weeks, 71% were undetectable. At 31 weeks the median CD4 count had
increased by 183 cells/mm3.
Abstract 697 — A clinical research center in Lagos, Nigeria
reported on 24-week experience treating 226 persons with generic
nevirapine, lamivudine and stavudine. Median viral load decreased
from 4.7 log copies/mL at baseline to 2.7 at week 24. Median CD4
count increased by 170 cells/mm3 and median BMI increased from 21.5
to 23.8. Adherence was reported as “good” in 74% of
patients.
Abstract 700 — A care center in Pointe-Noire, Congo conducted
a medical chart review of 49 patients who had received ART during
a period from April 2002 to January 2003. The majority (65%) received
a PI-containing regimen and 35% received an NNRTI-regimen. The mean
CD4 cell count/mm3 rose from 97 to 215 at six months; the proportion
of patients with CD4 below 50 fell from 45% to 4%. Mean patient
weight increased by 4.5 kg. Seven patients had side effects that
required a change in treatment. Side effects included disabling
peripheral neuropathy and acute pancreatitis.
Abstract 701 — Three primary care facilities in the South
African township of Khayelitsha run by MSF and the provincial government
reported on clinical outcomes for 288 adults who have received ART
since May 2001. Most patients started treatment with CD4 counts
below 50 cells/mm3. An 18-month survival estimate was 85%. Those
starting treatment with CD4 under 15 cells/mm3 had poorer survival
outcomes.
Abstracts 705, 1118 — A hospital pharmacy in Dakar, Senegal
assessed adherence and causes for ART interruption in 158 adult
patients over a three-year period. NNRTI-based regimens comprised
51% of prescriptions; PI-based regimens, 43%; dual therapy, 4%.
Ten percent of participants died and 2% withdrew. High adherence
was defined as mean monthly adherence of 95% or greater. The proportion
of highly adherent patients decreased as the duration of treatment
exceeded 12 months, as the monthly cost of treatment exceeded 15
euros ($17), or with the use of PI-containing regimens in patients
with advanced disease.
Access to Care through Research: After
the love is gone
In 1988, New York ACT UP treatment activist Jim Eigo argued,
“For the person with no other options, a research study
means access to healthcare.” This was a time in the
U.S. when the only way to get experimental treatments to prevent
certain deadly opportunistic infections was by joining a clinical
trial. The activist critique of the coercive nature of such
research led to a revolution in drug development and clinical
trial practice, including the assurance of active controls
and the innovation of expanded access programs. The availability
of marketed and experimental treatments has improved considerably
in the U.S. since then, at least for those who participate
in the healthcare system. But in many resource-poor parts
of the world, a research project may be the only way to access
lifesaving HIV healthcare — with or without sophisticated
antiretroviral medications.
One of the central ethical questions about performing research
in resource-limited settings is what happens once the research
is complete, recognizing that the influx of money, skills
and opportunities that come along with Western-supported research
can profoundly affect quality of life and expectations in
a place with few services. It’s generally agreed that
research projects should strive to leave behind improved capacity
to continue the benefits of research-associated services,
but the reality of what happens when the clinic closes is
not often reported.
A study recently detailed what happened to participants when
a long-term research project that provided primary health
care for participants in Lusaka, Zambia closed for seven months.
During the study, beginning in 1995 and continuing with one
break until 2002, serodiscordant couples were enrolled and
followed at three month intervals. The study has previously
reported that counseling and testing reduces the incidence
of HIV transmission in discordant couples by two-thirds. Couples
who entered the study were given primary healthcare at the
research clinic, which was lost when the study was interrupted.
In the report about the seven-month closing, death rates
and HIV and syphilis incidence were compared before, during
and after the closing during the period between December 1988
and June 1999. After the study reopened, 531 participants
(about 75% of those enrolled when the study was stopped) returned
and answered questions about their experience during the closing.
Most (82%) respondents reported continued condom use and the
incidence of new HIV and syphilis infections during the closure
did not differ from rates before or after. Yet the majority
of participants reported that the closing had a negative impact
on them, primarily due to the withdrawal of medical services.
Most strikingly, the death rate among HIV-positive participants
doubled from 6.7/100 patient years (PY) before the closing
to 12.4/100 PY during the closing, then went back to 7.5/100
PY after the study reopened.
This finding suggests the crucial role that medical management
can have on the outcome of HIV infection, even in the absence
of treatment. It also underlines the importance of assuring
the sustainability of interventions that accompany research
projects and for planning for the transition of study participants
to alternative sources of healthcare when project funding
ends.
Shutes E. What happens when a research project closes:
HIV incidence, mortality, and perceptions in a couples’
cohort in Lusaka, Zambia. The 2nd IAS Conference on HIV Pathogenesis
and Treatment, Paris, 2003. Abstract 111 |
Abstract 759 — A hospital in Maun, Botswanna evaluated predictors
of adherence with a review of 176 randomly selected patient records
of individuals who had received ART for 3 months or more. Adherence
measures included 7-day recall questionnaires and pill counts, which
were validated with pill identification tests, interviews and monthly
pill calendars. Overall, monthly average adherence was 24.9 adherent
days per month (83%). Factors that promoted adherence were adherence
partners, pharmacy counseling and pill counts. Non-adherence was
attributed to forgetting, lack of access, and lack of privacy.
Abstracts 1212, 1213, 1216 — The Botswanna national ARV therapy
program performed a retrospective chart review to analyze the experience
and outcomes of the first 306 people to receive ART in Gaborone
beginning in January 2002. All HIV-positive adult citizens of Botswanna
with CD4 counts below 200 cells/mm3 are eligible to receive an NNRTI-based
regimen for free, containing either nevirapine (47.5%) or efavirenz
(52.4%) plus Combivir. Women comprised 57% of the patients. At baseline
the mean CD4 count was 81 cells/mm3 and mean viral load was 5.65
log copies/mL. The median time of follow-up was 283 days. CD4 cell
count/mm3 increased by 166 at six months and by 204 at nine months.
Viral load fell below 400 copies/mL in 84.5% of patients at six
months. Anemia (grade 3 or 4) occurred in 8% of those receiving
Combivir; four patients died (mean time to toxicity 11.6 weeks).
Severe nevirapine-associated rash occurred in 3.42% (mean time to
toxicity 28 days). Nevirapine-associated hepatitis developed in
2.7% with two deaths (mean time to toxicity 12.6 weeks). Efavirenz-associated
CNS complications were reported in 4.45%. The overall death rate
to February 2003 was 10.7% (33 of 306) with an average time to death
after starting treatment of 2.4 months. Of those who died, 72% were
women. The overall baseline CD4 count of patients who died during
the period was 60 cells/mm3 (66% were below 50). The causes of mortality
among the 33 patients was wasting with chronic diarrhea (21.2%);
wasting without chronic diarrhea (9%); pulmonary TB (18.1%); AZT-induced
anemia (12.1%); nevirapine-induced hepatitis (3%); cryptococcal
meningitis (9%); TB meningitis (6%); Kaposi’s sarcoma (9%);
PCP (3%); pseudomonas pneumonia (3%); non-AZT-induced anemia (3%);
and suicide (3%). The authors note that limited blood supply for
transfusion are reflected in the high rate of AZT-associated anemia.
More frequent monitoring of hemoglobin for patients on AZT may also
be beneficial.
Abstract LB53 — The incidence of severe morbidity among members
of a research cohort in Abidjan, Cote d’Ivoire was compared
between 126 patients who had received ART after 1998, and 166 patients
with CD4 <200 who had received cotrimoxazole and were followed
between 1996 and 1998. The ART group composed of 81% women, had
a baseline median CD4 count of 137 cell/mm3 and were followed for
a mean time of 21 months. The non-ART group was composed of 60%
women, had a baseline median CD4 count of 100 cell/mm3 and was followed
for a mean time of 16 months. The most frequent causes of severe
illness in the groups were acute unexplained fever (ART vs. non-ART,
per 100 patient years): 12.2 vs. 9.1, severe bacterial diseases:
9.2 vs. 25, non-specific enteritis: 9.1 vs. 23 and tuberculosis:
2.4 vs. 6.9. The incidence of malaria was the same in both groups
(2.4 per 100 py).
References
Durier N, Treatment of HIV disease with HAART in Chiradzulu
District, Malawi. Abstract 112.
Ekong E, The Nigerian accelerated antiretroviral drug initiative
– evaluation of nevirapine, lamivudine and stavudine in ARV
naive patients. Abstract 629.
Azondekon A, HAART in Benin initiative: what have been used
and for whom? Lessons from 448 patients elected one year later.
Abstract 636.
Gahimbaza L. Costs and benefits of the antiretroviral therapy
in the private sector: the experience of Brarudi, Burundi. Abstract
668.
Mougnutou R, Evaluation of a HAART pilot study in Yaounde,
Cameroon: 24 months follow-up. Abstract 686.
Oyugi JH. Self-reported adherence measures are feasible and
valid compared to multiple objective measures in kampala, Uganda.
Abstract 690.
Kebba A. Therapeutic responses to AZT+3TC+EFV in advanced ARV-naive
HIV-1 infected Ugandans. Abstract 693.
Idigbe EO. The use of generic copies of ARVs in the management
of HIV infections in Lagos, Nigeria: a 6 month follwo-up study.
Abstract 697.
Kibangou N. Pointe-Noire, Congo-Brazzaville: ARV therapy assessment,
an evaluation following 6 months of prescription. Abstract 700.
Boulle A. Early outcomes and lessons from a public sector ARV
treatment programme in South Africa. Abstract 701.
Diop K. Adherence to ART in Senegal: assessment at the pharmacy
level. Abstract 705
Laniece I. Determinants of adherence among adults receiving
ARV drugs in Senegal (ANRS cohort study). Abstract 1118.
Nwokikr JI. Baseline data and predictors of adherence to ART
in Maun General Hospital, Maun, Botswana. Abstract 759.
Ndwapi N. Preliminary analysis of mortality and causes of death
among the first ARV-treatment naive HIV-1C-infected persons receiving
HAART under the Botswana national ARV treatment program. Abstract
1212.
Wester W. Preliminary analysis of toxicity and tolerability
among the first ARV-treatment naive HIV-1C-infected persons receiving
HAART under the Botswana national ARV treatment program. Abstract
1213.
Ndwapi N. Response to the Botswana national ART program - preliminary
analysis of the first 306 treatment -naive adults receiving HAART
via the national program. Abstract 1216.
Seyler C. Morbidity causes in HIV-infected adults before and
after the ART era in Abidjan, Cote d’Ivoire: Data from the
Cotrame ANRS 1203 cohort study. Abstract LB53.
Médecins Sans Frontières
(MSF) Antiretroviral Treatment Projects Worldwide
This is an excerpt from an MSF report entitled, Positive Replications,
which can be found in its entirety online at: www.accessmed-msf.org
The challenge of scaling up
There are many real and perceived barriers to expanding treatment
to large numbers of people in the developing world. Among those
most often referred to are lack of political will, the high price
of ARVs; the lack of trained staff and other elements of healthcare
infrastructure; the complexity of treatment protocols and laboratory
monitoring.
Médecins Sans Frontières (MSF) believes these should
not be viewed as reasons to accept the status quo. Despite facing
many of these problems in its HIV/AIDS treatment projects around
the developing world, MSF is showing that these barriers are not
insurmountable. In July 2002, MSF was treating 2,300 patients in
ten countries. At the Barcelona conference, MSF set itself the goal
of doubling the number of patients it treated by the end of 2003.
Now MSF has 23 projects in 14 countries with 4,447 patients (310
of these are children) receiving ART.
MSF’s most frequently used first-line regimen is stavudine,
lamivudine and nevirapine and fixed dose versions of these combinations
are being used in a majority of projects. In MSF projects the price
of first-line therapies ranges from US $277 (Cameroon) to US $593
(Ukraine) per patient per year.
Médecins Sans Frontières has been caring for people
living with HIV/AIDS in developing countries since the early 1990s,
and the first ARV treatment projects began in 2000. As of June 2003
more than 5,000 people have received ARVs in MSF projects. Eighty
eight percent of these are still on treatment.
Although the places and contexts are very different for each of
these treatment projects, a certain number of common denominators
exist: MSF focuses on offering care to the poorest and most destitute
people; and to ensure that a maximum number of people can be treated
and that programmes are sustainable, efforts are made to identify
the least expensive sources of medicines. In many cases, this means
using generic versions of ARVs.
MSF does not offer ART in a vacuum, but instead aims to integrate
treatment into a continuum of care: projects include prevention
efforts (health education, prevention of mother-to-child transmission
of HIV), voluntary counselling and testing (VCT), treatment of opportunistic
infections, ART and nutritional and psychosocial support.
MSF treats people with antiretroviral drugs in its projects
in the following countries (June 2003 figures):
|
| Country |
Place |
All patients |
Children |
| Cambodia |
Phnom Penh, Siem Reap, Sotnikum |
736 |
28 |
| Cameroon |
Yaoundé, Douala |
281 |
7 |
| Guatemala |
2 projects in Guatemala City; Costepeque |
421 |
0 |
| Honduras |
Tela |
118 |
17 |
| Kenya |
Homa Bay, Mathare, Nairobi |
461 |
29 |
| Malawi |
Chiradzulu, Thiolo |
731 |
59 |
| Mozambique |
2 projects in Maputo; Tete; Angonia |
130 |
3 |
| South Africa |
Khayelitsha |
480 |
60 |
| Thailand |
Bangkok, Surin |
717 |
86 |
| Uganda |
Arua |
305 |
1 |
| Ukraine |
Odessa, Mykolayiav, Crimea |
20 |
20 |
| |
|
|
|
| New country projects |
|
|
|
| Burkina Faso |
Ouagadougou |
20 |
0 |
| Burma |
Kachin, Rangoon, Shan, Rakhine states |
25 |
0 |
| Indonesia |
Merauke |
2 |
0 |
| |
|
|
|
| Total number of patients |
|
4,447 |
310 |
Notes on Hepatitis C Infection
from the IAS Paris Conference
By Tracy Swan
Two Viruses, One Clean Syringe and a Condom
Hepatitis C infection is prevalent among injection drug users around
the world, and in the United States, as many as 90 percent of the
people who acquired HIV from injection drug use also have hepatitis
C virus (HCV). Overall, 16–25 percent of people with HIV in
the U.S. are also coinfected with HCV. In China, 96 percent of HCV
infections resulted from injection drug use and/or illegal blood
donation; in Tunisia, injection drug use was reported by 83.7 percent
of coinfected people, and in Brazil, male and female HIV-positive
injection drug users were far more likely to be coinfected than
people who acquired HIV from sex.
Overall, sexual transmission of hepatitis C appears to be low,
but has been reported more frequently among men who have sex with
men (MSM). In England, researchers have tracked cases of acute hepatitis
C infections between 1997 and 2002 among a group of MSM. Of the
28 cases identified, 26 were in HIV-positive men, and 20/26 reported
no risk factor other than unprotected anal intercourse. Another
group of researchers in England identified 20 cases of acute HCV
in HIV-positive men between October of 2002 and January of 2003.
All 20 had had unprotected anal intercourse; 15 of the 20 reported
fisting. Although the possibility of sexual transmission of HCV
has been debated in the past, clearly, HCV prevention messages targeted
specifically for MSM are now overdue.
As prevention, education and treatment programs for HIV begin to
scale up in the developing world, the challenge of HCV must not
be forgotten. At a minimum, access to clean injection equipment
should be included in prevention and treatment initiatives. But
scaling-up of prevention efforts is urgently needed here in the
United States as well. Clean injection equipment must be readily
available to all who need it in sufficient quantities with minimal
legal and bureaucratic barriers to access. Imagine what would happen
to the HIV infection rate be if obtaining protection required exchanging
used condoms on a one-to-one basis!
HIV, HCV, Injection Drug use and Survival in the HAART
era
End-stage liver disease has become a leading cause of death among
HIV-positive people in Europe and the United States, and the liver
damage caused by hepatitis C disease progresses more rapidly in
HIV-positive people. One study found advanced liver disease among
a third of 914 coinfected individuals, all of whom had a similar
estimated duration of infection (16 years). Heavy alcohol intake
and increased age (over 35) were the only variables associated with
the progression of fibrosis, the tissue scarring that accompanies
HCV infection.
A French group evaluated a decade of data from 2, 710 HIV-positive
individuals, and analyzed the impact of HAART, HCV coinfection and
injection drug use on survival before and after 1996. During the
HAART era, five-year mortality rates were higher for coinfected
people than for those with HIV alone, and higher yet for coinfected
injection drug users. Although HCV coinfection did not significantly
increase the risk of death at five years, coinfection plus injection
drug use did, with the risk of death almost three times greater
for coinfected injection drug users than for people with HIV alone.
Reports of HIV/HCV
coinfection prevalence from around the world
|
| Region |
|
HCV Prevalence* |
| Abidjan (West Africa) |
pregnant women: 501 HIV-positive
pregnant women: 501 HIV-negative |
1.2% (6/510) HIV/HCV
1% (5/501) HCV only |
| Cameroon |
pregnant women: 217 HIV-positive
pregnant women: 2,337 HIV-negative |
1.8% (4/217) HIV/HCV
1.9% (45/2337) HCV only |
| China |
|
56.9% (136/239) |
| Indonesia (Jakarta) |
|
62% (74/162) |
| Southern Brazil (Porto Alegre) |
|
28.5% (321/1128) |
| Spain |
|
64.6% (973/1506) |
| Thailand |
pregnant women: 1437 HIV-positive
pregnant women: 448 HIV-negative |
2.9% (42/1437) HIV/HCV
0.5% (2/448) HCV only |
| Tunisia |
|
43% (80/186) |
| *all HIV-positive except where indicated |
|
These differences in survival may be attributed to several factors.
Some studies have reported that coinfected people have a blunted
immune response to HAART which might mean they are more susceptible
to death from AIDS. Also, coinfected individuals are at greater
risk for developing liver toxicity from antiretroviral therapy and
they may experience more frequent switches or discontinuations of
drug regimens. Access to treatment for HIV and HCV is a significant
problem for coinfected injection drug users, who often receive HAART
later than non-users. Until 2002, injection drug use was a contraindication
for HCV treatment and although the 2002 Consensus Statement on Management
of HCV has revised this recommendation, many physicians are still
reluctant to treat injection drug users. Even when HCV treatment
is prescribed, access is not guaranteed; under-funded AIDS Drug
Assistance Programs can’t afford to add expensive HCV treatment
to their formularies, leaving many coinfected people without a way
to pay for HCV therapy, which costs as much as $40,000 for the 48-week
course of treatment. These factors, plus the primary risks of using
injection drugs probably all contribute to higher death rates for
this vulnerable group.
Lack of access is not the only barrier to HCV treatment. Eligibility
can be limited; a Spanish study reported that 60.6 percent of 1,006
coinfected individuals had contraindications for HCV treatment.
Furthermore, the side effects of interferon and ribavirin may be
especially severe in coinfected persons. In the studies presented
at the IAS conference, the rate of treatment discontinuations ranged
from 15 to 24 percent and adverse events reported included psychiatric
toxicities, pancreatitis/lactic acidosis, hepatic decompensation,
severe neutropenia, thyroid dysfunction and retinopathy.
HCV treatment does not appear to work as well in coinfected people
regardless of CD4 cell count or HIV virus load. In one study, only
21 percent (28/132) of individuals treated for HCV achieved a sustained
virologic response six months after completion of a 48-week course
of standard interferon plus ribavirin. Disappointingly, with pegylated
interferon and ribavirin, only 26 percent (15/58) of individuals
achieved a sustained virologic response. The only predictive marker
that has been significantly associated with sustained virologic
response to treatment remains infection with HCV genotype 2 or HCV
genotype 3.
References
Kilani B. Seroepidemiology of HCV-HIV Co-Infection in Tunisia.
Abstract 952.
Yin N. Epidemiology and Distribution of Human Immunodeficiency
Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV) Among Intravenous
Drug Users and Illegal Blood Donors in China. Abstract 954.
Bhagani S. Acute HCV in a Cohort of HIV-Positive Homosexual
Men in a London Clinic-Risk Factors and Outcomes. Abstract 955.
Voirin N. Survival of Patients infected with HIV and HCV in
the era of highly-active antiretroviral therapy. Abstract 956.
Berenguer J. Interferon Alpha and Ribavirin Therapy for Chronic
Hepatitis C in HIV-Infected Patients (GESIDA 28-02 Study). Abstract
960.
Njouom R. Seroprevalence of HCV Among HIV-Positive and HIV-Negative
Pregnant Women in Yaounde, Cameroon. Abstract 967.
Hernández S. Estimation of the HCV-HIV Co-Infected Population
Eligible for Anti-Hepatitis C Treatment or Liver Transplant in Spain
(GESIDA 28-02 Study). Abstract 970.
Parra-Ruiz J. IT78047 Trial. A Randomized, Multicentre Study
of Pegylated Interferon Plus Two Different Does of Ribavirin in
the Treatment of Patients with Chronic Hepatitis C and HIV Infection.
Abstract 971.
Browne RE. Increasing Incidence of Acute Hepatitis C in HIV
Positive Men Secondary to Sexual Transmission: A New Epidemic? Abstract
972.
Hopkins S. HIV-HCV Co-Infection: To Treat or Not to Treat.
Abstract 973.
Msellati P. Prevalence of Hepatitis B and C Viruses and HCV Genotypes
in HIV-Positive and Negative Pregnant Women in Abidjan, Ivory Coast
(West Africa). Abstract 974.
Voigt E. Factors Related to Outcome of Treatment with Pegylated
Interferon Alpha 2b (PEG INF) Plus Ribavirin (RBV) in HCV/HIV Co-Infected
Patients. Abstract 976.
Slim J. Neutropenia as an Adverse Drug Reaction in Patients
Co-Infected with HIV/HCV Receiving Interferon and Ribavirin Therapy.
Abstract 977.
Sprinz E. Hepatitis C Virus Infection in a Southern Brazilian Cohort
of HIV-Infected Patients. Abstract 978.
Martin-Carbonero L. Fibrosis Progression in 914 HIV-HCV Co-Infected
Patients is Strongly Related With Age: A European Collaborative
Study. Abstract 984.
Pacheco R. Clinical and Epidemiological Characteristics of
Hepatitis C Infection in a Large Cohort of HIV-Infected Patients
in Spain (GESIDA 29/02 Study). Abstract 985.
Birowo NR. Prevalence of HIV and HCV Co-Infection Among Drug
Users. Abstract 987.
Ngo-Giang-Huong N. HIV-1/HCV Co-Infection in Pregnant Women
and Their Infants in Thailand. Abstract 994.
Preventing HIV/AIDS in India:
Points to Ponder
By Maitreya
These notes were prepared on the occasion of the International
Conference of South Asian Parliamentarians (SAARC) meeting on the
“Advocacy Role of Elected Representatives in Prevention of
HIV/AIDS”, August 1-2, 2003, Ashok Hotel, New Delhi (India).
The person writing this letter has some experience gained in prevention
activities against the spread of HIV/AIDS in India during the last
eight years. Initially the Government and funding agencies came
along in a big way addressing the issue of HIV through prevention
projects. During the course of implementing these top down projects,
myself and my organization felt some severe inadequacies starting
with the conceptualization, to the implementation and down to preparations
on the ground. In short, in project lingo, these are lessens learned.
Targeted intervention among “high-risk groups”
This is a highly effective intervention strategy. Since HIV is
transmitted through blood and sexual intercourse, to address the
high-risk groups (sex workers; injecting drug addicts; mobile work
force, such as truck drivers, construction workers etc.) on a war
footing before HIV percolates into the general public would seem
effective. But we failed miserably in preparing the ground for intervention.
Take for example, the case of sex workers; we never addressed the
laws criminalizing sex work and its premises, stigma attached to
sex work, human rights violations both by the public and police,
gender-power relations in sexuality and differences among the different
segments of sex workers. No project can work effectively in a criminalized
atmosphere. The projects existed in India as clandestine activity
just like contrabands. There never developed a co-ordination between
the law making/implementing authorities and the health departments.
The projects were designed in the context of brothels in Europe
or U.S., where there is relative freedom for the inmates in deciding
their personal matters. But here the situation was of slave trade
and there is no organization of sex workers for collective bargaining
either with the brothel owners or with the clients. Without a sex
worker’s organization they can never bargain with clients;
if one denies, another should not cater. Except perhaps in few pockets
like Sonagachi in Kolkata, or in some fifty-odd sites in West Bengal,
Sangli in Maharashtra, sex worker’s organizations are non-existent
in India. Here again, we could see the relative freedom of sex workers
running the brothels to decide the matters. But the Government’s
policy is still against the sex worker’s rights and organizations.
Again, the projects drawn in the situation of brothels are used
to address the situation of street-based sex workers, for example
in Kerala, where there is no red-light area or permanent brothel.
All the parameters and monitoring systems are for brothels, which
makes it ridiculous. (For example, in a brothel situation, condom
tracking with a waste basket outside a room can provide some information,
but in the street, this exercise is a joke — still the project
reports will be full of condom tracking.) In the absence of brothels,
drop-in-centers are a must for executing the projects. But as there
was no ground preparation from the part of Government in supporting
the drop-in-centers, it vanished from the projects in the course
of implementation. This means there is no collectivity and hence
no bargaining in condom use. There is only a nascent organization
in Kerala, but projects go on in papers.
In the absence of collective bargaining the only alternative is
using condoms oneself. But the condoms supplied to the female sex
workers are male condoms, which means they have to ask the clients,
under harrying conditions, to wear them. The power relations in
sexuality are against the women; all they could do is wear something
themselves. If the Government promoted female condoms in targeted
interventions it would have succeeded immensely. They will cite
the prohibitive cost but mass production and subsidy could have
brought down the cost. In a study, it is shown that tampons can
reduce the rate of infection in women. So the Government should
also provide these along with female condoms in the projects and
ensure their availability in the market.
There is still no concept of Male Sex Workers (MSW) but only of
Men Seeking Men or Men having Sex with Men (MSM). This stems from
the assumption that sex workers are only women; again no one sees
it as sex work but only as exploitation of women, because if you
admit the reality of sex work, then the strategy and policy will
have to change. So the authorities just shut their eyes conveniently
against the reality. But those who are involved in sex work, whether
they are male or female, know it as work. So we should understand
that there is a distinct category of male sex workers, who should
be addressed independently. (We are not talking of gigolos, a minuscule
category, which caters to rich independent women.) We should also
know that we can’t address all gay men as sex workers or vice
versa. Right now there is confusion in these MSM projects.
Again, archaic criminalizing laws coined in the name of “unnatural
offences” hinder all activities among the male sex workers
as well as within the gay community. There are instances of health
activists getting arrested on these charges. The concept of needle
exchange among IV drug users is still being debated. With the existing
laws, as in the case of sex workers, no project can be implemented
with effectiveness. Change of law is a must in these situations.
Condom promotion
The concept of A (Abstinence) B (Be faithful to one partner) C
(then use Condoms if you can’t stick to the other two) in
prevention projects ran high. All the IEC (information, education
and communication) materials produced by the State Aids Control
Societies (SACS) had this moral overtone in it. I must say they
created fear and shame in people on the whole. Now it is backfiring.
People are rejecting their kith and kin and in the case of strangers
they even go to the extent of lynching them. The presumed “Indian
Culture” and morals are actually fallout of our colonial past.
The Indians, and for that matter people of other countries also,
have a rich tradition in sexuality and a practice quite diverse.
But the prudish postures our administrators take make them fit enough
to be living in 19th Century Victorian England. Because of this
“right” moral approach, people hide their sexuality
and pretend otherwise. The existence of several million female sex
workers along with millions of all other varieties in India show
that we have a highly promiscuous way of life. We all pretend that
we have the barest minimum of sexual life and only the “westerners”
are indulging in sex. If it is true, then how come we Asians have
two-thirds of the world population? We should know that we are more
active in sex and for that matter, more in penetrative sex, and
for that matter, more active in unsafe sex than all the people in
the world. So it is imperative to promote condoms in every way possible
and also to teach non-penetrative sex. Think about promoting kissing
in the movies and tell people to indulge in non-penetrative sex.
Make sexuality a pleasurable act, which could be safely practiced
instead of keeping it as an act of procreation. Keeping sex as an
act of procreation, as religion preaches, is keeping people in the
animal state. Because, Westerners were able to conceive sex as pleasure
in their culture they have brought the burgeoning population in
their countries under control. Here, even after thirty years of
condom promotion in the family welfare scenario, condoms have failed
to click because of the opposite understanding. For us sex first
means procreation and penetrative sex. Just think about all the
literature like Kamasutra and all the temples of Khajooraho and
Konark, what a fall! A real fall from heaven. What we call now Western
is Indian and what we call Indian is Western.
When we talk of condoms, we have to think about varieties. We should
invent different varieties, especially different colors to suit
the Asians. We can do away with the white variety altogether, or
maybe keep a few for the pale skin people. We must immediately produce
flavored condoms and thus promote oral sex, another safe sex activity.
As I said earlier, we must produce female condoms and tampons to
give our women a defense against the penetrative sex culture of
the males. This will remain as a viable alternative for the meek
and submissive “wives” and “girl friends”.
Look at the varieties now available in the market, ribbed condoms,
spotted condoms, dotted condoms etc. The idea of friction inside
the vagina is behind all this, which the male thinks is a necessity
for women. Poor women have to bear all this thrusting and just burn
inside. Can’t these fellows who design these condoms, just
ask the women? Haven’t they heard about a protuberance called
clitoris in women? Didn’t they know about the Grafenberg spot
(G-spot) in women’s vagina? Ignorance of women’s sexuality
is the principal input in the designs of men’s condoms now.
We have to consult women when designing male condoms. Similarly,
we should consult men when designing female condoms!
Foundation for Integrated Research in Mental
Health (FIRM), Kerala, India
Email: maitreya@asianetindia.com
Stumbling Forward: New Drugs Bring
New Questions
By Bob Huff
Viread, Viread, Viread
Viread (tenofovir disoproxil fumarate) has come under a lot of
scrutiny this summer after reports of pharmacokinetic interactions,
creatinine increases, and a strange case of bad clinical chemistry
with abacavir and 3TC set off a flurry of “Dear Doctor”
letters.
First, Viread is turning out to have more pharmacological interactions
than were understood at first. An interaction with Videx EC (ddI)
has been recognized to raise ddI levels and a letter from Bristol-Myers
Squib (BMS) recommends separating Viread dosing by two hours before
or one hour after taking ddI. Some doctors have reduced dosing of
Videx EC from 400mg to 250mg once-a-day taken simultaneously with
Viread, but, so far, there is no clinical trial data to validate
this approach.
Bristol also issued a Dear Doctor letter advising of a pharmacokinetic
interaction between tenofovir and the new BMS protease inhibitor,
atazanavir (Reyataz). This is strange because tenofovir is excreted
through the kidneys and was not expected to affect drugs metabolized
by the liver. A BMS-funded study found that, 24 hours after taking
a dose, when blood levels are lowest (Cmin), concentrations of atazanavir
(400mg) coadministered with tenofovir were 40 percent less than
when given alone in uninfected persons. The wide variability of
the Cmin of atazanavir was a topic of concern for the FDA antiviral
advisory committee that evaluated the drug prior to approval. Some
members of the panel were worried that atazanavir Cmins would be
too low in too many people to prevent virologic breakthrough.
BMS advises that clinicians should use caution when administering
atazanavir with tenofovir. As once-a-day drugs, the two seem like
natural allies but the unboosted combination should probably be
avoided until someone can definitively explain what’s going
on and how to dose around the problem. The letter also reported
that blood levels of tenofovir were raised by coadministration with
atazanavir, although no increase in tenofovir-associated toxicity
was noted at 24 weeks.
But all may not be lost. Preliminary data from BMS has shown that
boosting atazanavir with ritonavir (300mg/100mg) raised Cmins to
more comfortable levels. A study by a French group cited in the
BMS letter found that the Cmin of boosted atazanavir was decreased
by about 23 percent in people with HIV. BMS advises that if atazanavir
is to be coadministered with tenofovir ”consideration should
be given to administering Reyataz 300mg with ritonavir 100mg until
additional data are obtained.“ The drugs should be given as
a single daily dose with food.
As an aside, at the IAS Conference in Paris, data was presented
that suggests that the 100mg ritonavir booster dose, while compromising
atazanavir’s benign lipid profile a little bit, does not have
a huge effect and that the combination may be more tolerable than
Kaletra. Still, there is not enough being done to get the message
out that unboosted atazanavir poses a big risk for someone who’s
been on PIs in the past and may harbor resistance mutations. For
an individual coming off of a treatment interruption or a PI-sparing
regimen a current genotype might not show hidden PI-resistant strains
waiting to bloom once atazanavir is started. Activists are concerned
that with all the hoopla about once-daily convenience, these dosing
concerns will be overlooked.
The Tenofovir / Abacavir Debacle
In the mad race to achieve reliable once-daily dosing with novel
combinations, more victims are being left on the roadside. There
was a peculiar little study presented at the IAS Conference in Paris
that set off alarms about combining Viread and Ziagen (abacavir)
and 3TC (Epivir, lamivudine) in a QD combo. A 19-person, non-randomized,
uncontrolled pilot study was undertaken by Charles Farthing of the
AIDS Healthcare Foundation. Patients were put on a once-a-day triple-NRTI
combination of abacavir, tenofovir and 3TC and then observed to
see what would happen. It failed spectacularly. Within 8 weeks over
half of the people in the trial had virological failure and the
study was stopped.
Simultaneously, GlaxoSmithKline (GSK), the maker of abacavir and
3TC was performing a much larger, randomized, but no less peculiar
study comparing tenofovir to efavirenz, each with a background of
abacavir and 3TC. Again the tenofovir/abacavir combination collapsed
with about half failing at the 8-week mark and the 200-person study
was stopped. Another French study is rumored to report similar results
soon.
There are a number of aspects to the design of these studies that
are disconcerting. First, abacavir was used as a once-daily drug
with little data to support that. Second, this particular triple
combination hadn’t been properly studied even as a twice-daily
regimen. Finally, a number of the people enrolled had viral loads
in excess of 100,000 copies — a population not expected to
do well on a marginally potent regimen. The result is that several
patients now have resistance to 3TC, abacavir and tenofovir.
In justification of these studies, it could be said that many people
expected this should have been a potent and convenient combination,
and it’s one that some clinicians had already been using in
the absence of data. For Glaxo, an added incentive for undertaking
the multi-million dollar trial was to generate some numbers that
would make Viread look bad. Who seriously thought tenofovir was
a match for efavirenz? But with a coformulated tenofovir and FTC
tablet expected from drugmaker Gilead Sciences next year, Glaxo
may have been seeking ammunition to protect its market-dominating
Combivir from an upstart. As for AHF, some have speculated that
the failed study was actually a ploy to discourage abacavir use
or a petulant bid to avoid AZT. Last year AHF sued Glaxo, ostensibly
over their AZT patents (the original case was tossed), in a move
some say was a tactic to punish Glaxo for refusing to fund the Foundation’s
international expansion. (AHF has launched clinics in Uganda and
South Africa, which are in the process of scaling up to treat over
1000 people.)
To Glaxo’s credit, when it realized there was a problem,
the company issued a Dear Doctor letter warning about the combination.
According to Glaxo, their study began enrolling in January of 2003
and by the last week in June, the first few reports of virologic
failure had been received. At that time, the company amended the
protocol to call for more frequent monitoring and the study continued.
Then, on July 3, one doctor called and said he had 9 patients who
appeared to be failing the tenofovir arm. This sent Glaxo into a
state of alert and the company began collecting patient data for
a preliminary analysis. That same day the IAS abstract book was
published and the company learned that the title of Farthing’s
talk scheduled for July 14th seemed to confirm that there was a
problem. On Thursday, July 10, with most of the Glaxo investigators
in Paris for the IAS conference, the emergency data analysis reported
that the catastrophe was real and the study’s global safety
board ordered the trial stopped. Gilead was informed of the situation
and they reported that they had heard rumors that a French study
was having similar results. By Friday, July 11, Glaxo began notifying
study investigators and briefed U.S. community representatives on
Sunday the 13th. On Monday, Glaxo met with Farthing to show him
the data supporting his findings and he included a reference to
the larger trial during his presentation that afternoon.
Farthing would have submitted his abstract for the July conference
sometime before the deadline in March. Gilead says they became aware
of his results in the Spring but decided not to tell Glaxo because
they thought it would be dangerous to draw conclusions based on
that small amount of data. Yet had Glaxo known they might have increased
their vigilance for problems and could have begun investigating
the mechanism sooner.
The reason for the bad outcomes with this combination are subject
to wide-ranging speculation pending further research. Gilead said
they did a small pharmacokinetics study of tenofovir and abacavir
but didn’t observe an interaction. Farthing offered that the
problem may lie with once-daily dosing of abacavir or perhaps 3TC.
Glaxo suspects a shared resistance pathway of abacavir and tenofovir
may be the culprit and cites evidence from a successful study of
tenofovir plus Trizivir (abacavir/ 3TC/AZT) to suggest that AZT
may play a protective role in preventing resistance. It would be
welcome news if a credible, fourth party stepped into this question
to figure out what is really going on. Glaxo will present a case-by-case
analysis of their study at the ICAAC conference in September.
Yet More on Viread
As for tenofovir on its own, new concerns have been raised about
the drug’s effects on the kidneys after a large cohort study
reported frequent mild elevations of creatinine levels. Julio Montaner
conducted a study of 310 patients in Vancouver who received tenofovir
on expanded access during 2002 and compared them to 404 patients
who started abacavir during the same period. Within six months of
starting therapy creatinine elevations greater than 1.5 times above
baseline were seen in 8.4 percent of those starting tenofovir and
in only 3.6 percent of those who stated abacavir. A lower baseline
CD4 count was associated with a greater risk of a creatinine elevation.
Nephrologists that examined the Canadian cohort data saw no indication
of Fanconi’s syndrome or serious kidney impairment, yet physicians
are now advised to pay careful attention to creatinine levels and
to be vigilant for signs of kidney problems in patients on Viread.
Will Miracles Never Cease?
Gilead was reportedly slapped on the wrist by the FDA for sloppy
statements made by sales reps downplaying the potential for developing
lactic acidosis and hepatic steatosis while on tenofovir. All NRTIs
carry an FDA warning about the rare but deadly possibility of developing
these NRTI-associated conditions. In another incident, Reuters reports
that Gilead sales reps were cited by the FDA for pitching Viread
as a “miracle drug.” There are no clinical data to support
the claim.
Emtriva Approved
In happier Gilead news, Emtriva (FTC, emtricitabine) was approved
by the FDA on July 2. The drug is a nucleoside analog reverse transcriptase
inhibitor (NRTI) comparable to 3TC (Epivir) in its resistance profile
but with somewhat increased potency and a longer half-life allowing
for comfortable once-daily dosing. The drug also exhibited less
toxicity to mitochondria in laboratory tests. Despite the similarity
to Epivir, more needs to be learned about Emtriva and its resistance
profile. The sooner FTC is added to the commercial phenotypic assay
panels and clinical cutoffs start to become clear, the sooner we
may begin to appreciate the nuances of Emtriva’s particular
resistance characteristics. All in all, the incremental benefits
of FTC over 3TC should make Emtriva a welcome addition to the HIV
medicine shelf, although caution is always warranted when a new
drug is released since rare side effects may not show up until the
drug has been in broader use over longer periods of time. One odd
side effect that has been reported is a spotted discoloration on
the palms of the hands of people taking Emtriva.
Fuzeon Forges Ahead
Four months after its FDA approval, prescriptions for Fuzeon (enfuvirtide,
T-20) are being filled at a steady pace, says Roche. Interestingly,
after all the concern about having enough T-20 to meet the demand,
Roche has announced that production capacity has been increased
and was now capable of supplying Fuzeon to nearly 20,000 people
by the end of 2004.
Reports on 48-week data from the large, pivotal TORO 1 and TORO
2 trials confirmed 24-week results with about twice as many Fuzeon
patients experiencing a greater than 1.0 log reduction in viral
load as those receiving optimized background therapy without Fuzeon.
The median time to virologic failure was 32 weeks for patients receiving
Fuzeon vs. 11 weeks for patients receiving the background regimen
alone. However, while 47 percent of Fuzeon recipients had achieved
at least a 1.0 log reduction at 24 weeks, at 48 weeks this proportion
had dropped to 34 percent which indicates the fragile durability
of these salvage regimens.
Julio Montaner presented an analysis of factors that predicted
success with Fuzeon in the TORO trials at the 24-week mark. Patients
with CD4 counts over 100 and those with at least two active drugs
in their background regimen were less likely to have virologic failure.
This analysis reinforces the problem with finding a therapeutic
niche for T-20: those who need it most are less likely to have an
optimal outcome, and those who will be most likely to do well on
Fuzeon may be unwilling to undergo the burdens of twice-daily injection.
Other factors that predicted success were viral load below 100,000
and no prior exposure to Kaletra.
One oddity uncovered in the TORO trials was that the incidence
of bacterial pneumonia, which had been recognized in earlier reports,
was now 10 times higher in Fuzeon patients (6.6% vs. 0.6%) reaching
10 percent in those with CD4 counts under 200. Possible reasons
for this are under investigation. In the meantime, Roche should
be reminding doctors to watch for early symptoms of bacterial pneumonia
in people who are starting Fuzeon.
Tipranavir Access Improves Slightly
According to Boehringer Ingelheim, enrollment in the RESIST Phase
III trials for tipranavir is on track for completion by the end
of the year. An open label safety study (OLSS) is now accepting
persons who could benefit from tipranavir but were unable to participate
in the large studies. The capacity of the OLSS has recently been
doubled, which will allow 600 patients worldwide to enroll during
2003. Still, drug supply problems make a less-restrictive expanded
access unlikely until the first part of 2004 when the company expects
to be able to add an additional 50 persons per month. By the middle
of 2004 the expanded access program is projected to be able to add
100 patients per month until approval sometime in 2005. As Julio
Montaner’s analysis suggests, access to tipranavir will be
especially crucial for individuals considering starting Fuzeon if
they are not susceptible to other available protease inhibitors.
Wrong Path for Guidelines?
The U.S. guidelines were released during the IAS meeting where
they made nary a ripple. The biggest news is that now only efavirenz
or Kaletra-based regimens are recommend for first-line, first-time
therapy. And, despite mounting evidence and clinical consensus that
d4T is not the best choice for treatment-naïve patients with
healthy immune systems, Zerit was still listed among the preferred
drugs with only an asterisk to indicate its association with lipid
abnormalities. By all accounts the guidelines development process
can be a political snake pit, with industry partisans lobbying for
this drug or that. At a minimum the guidelines reflect a reasonable,
conservative take on how to approach therapy and what not to do.
For those who take time to read them, they provide an education
in the complexities behind making treatment decisions. The problem
is that many physicians may never read them thoroughly. Table 12a
(Antiretroviral Regimens Recommended for Treatment of HIV-1 Infection
in Antiretroviral Naïve Patients) is such an easy pill to swallow.
That’s where you can catch the new first-line drug recommendations
at a glance. This table is destined to appear on a thousand power-point
slides. Already I have received an email from a PR firm repping
Abbott that included a disembodied copy of Table 12a. Oddly, the
stavudine asterisk was in place but it led nowhere. So there was
the take-home message untroubled by messy footnotes: Kaletra plus
Epivir and AZT or Zerit highly recommended, and the lipids be damned.
The new guidelines had been expected at the Retrovirus Conference
in February. It’s unfortunate that they arrived just as several
new products hit the market. With few of 2003’s new drugs
mentioned (Fuzeon is discussed in the context of treating ARV-experienced
patients), and efficacy still paramount, the new guidelines seem
to lag behind the times a bit. For a set of authoritative guidelines
that catches up with more contemporary thinking, consult the British
HIV Association, which doesn’t mince words when it comes to
Zerit: “For initial therapy, combinations including D4T are
not recommended because of increasing evidence of its role in the
development of lipodystrophy and abnormal lipid profiles.”
Progress at Last? South Africa
Relents on HIV Drugs
By Bob Huff
An announcement has been made. Is that enough to finally stop the
river of death in South Africa? After years of refusal, the government
there has asked that a plan be developed to bring antiretroviral
drugs to several million of its citizens who will surely die if
their HIV disease continues untreated. At a pace of over 1000 deaths
per day in a country twice the size of Texas, the mortality rate
in South Africa has not yet peaked, and hundreds of thousands more
will surely die before the plan is written, the implementation rolled
out, and the drugs begin to flow to hospitals and clinics.
It’s still only an announcement to make a plan, but it feels
like a glacier has tumbled into the sea. The battle to treat the
dying in South Africa has been long and tragically unnecessary.
This is a country where apparently nothing comes easily, but persistence
is rewarded. After an 80-year struggle to defeat the institutionalized
racism of apartheid, a new government finally emerged in 1994 led
by a freedom fighter schooled on a windswept prison island in Capetown’s
Table Bay. Nelson Mandela, a hero and living saint, led the country
through the transition to freedom with vision and magnanimity —
and South Africa survived. But as liberation found its feet, HIV
was flourishing, scarcely noticed, sweeping through the cities,
townships and countryside.
Unfortunately, Mandela’s presidency never seriously addressed
HIV as infection rates ran unchecked and prevalence soared to a
quarter and then to half of the population in some areas. Because
AIDS is a slow disease, the stark horror of the rising death toll
was deferred until Mandela had been succeeded by a new president,
Thabo Mbeki, a political leader who had been formed, not on Robben
Island, but in the best European and Russian schools of economics
and revolution.
In the late 1990s, seeing that the miracle of antiretroviral drugs
was preventing death in the rich, northern countries, groups of
doctors and activists began to call upon the South African government
to recognize the crisis and avert millions of deaths by finding
a way to bring medicines to the townships. A new generation of heroes
emerged to take up this struggle, most famously Zackie Achmat, who
vowed to not treat his own HIV disease until antiretrovirals were
available to all his countrymen.
The challenge was immense. The prices for AIDS drugs in the North
were completely unaffordable for South Africa, and the international
drug makers resisted coming to a practical accommodation because
they feared that their markets in the rich countries would be hurt
if cheap drugs were diverted to Northern pharmacies. They also were
bound to serve and protect the emerging international system of
intellectual property protection that was being designed by the
World Trade Organization. Already, Brazil was tackling its own HIV
crisis by ignoring patents and making affordable generic copies
of AIDS drugs at home to treat its hundred thousand citizens who
would die without them. Generic makers in India were gearing up
to make the drugs available for pennies on the dollar of what the
majors charged. Threatened, the corporations blindly fought back
without a thought for the cost.
The activist Treatment Action Campaign (TAC) began to graphically
demonstrate that HIV treatment was crucial and feasible in South
Africa. Achmat and others smuggled generic fluconazole from Thailand
to help people dying horrible deaths from AIDS-related cryptococcal
meningitis. Pfizer, the official maker of fluconazole, refused to
make the drug available at a reasonable rate until TAC’s defiance
and publicity exposed their stance. When it came to HIV drugs, the
pharmaceutical industry responded with a policy of obstruction and
disinformation. They dismissed claims that prices or patents were
the problem, arguing that clean water and infrastructure of the
sort found in industrialized nations needed to be in place before
complicated antiretroviral drugs could be introduced. Industry apologists
in the U.S. government publicly doubted if Africans could learn
to tell time. In South Africa, led by GlaxoSmithKline, the big pharmaceutical
companies joined a lawsuit to defend their market and block affordable
generic drugs from entering the country.
Taken alone, the deadly obstruction of the drug industry could
have been surmounted. Eventually, as generic drugs became available,
market forces, activist pressure and public opinion compelled the
big companies to drop the lawsuits and lower prices. Affordability
unlocked a wave of small pilot treatment programs using generic
drugs that demonstrated that antiretroviral therapy in a resource-poor
setting was feasible and effective. A few lives were finally being
saved. But, tragically, the South Africans faced a much more formidable
obstruction in one who should have been an ally: President Thabo
Mbeki.
In 2000, a year when the International AIDS Conference was finally
to be held below the equator in the heart of South Africa’s
epidemic in Durban, and just as the world seemed poised to respond
to the wildfire consuming the region, Thabo Mbeki revealed that
he had found evidence on the Internet saying that HIV was not really
what was killing so many of his people; that the problem was actually
poor nutrition and tragic history; “a uniquely African catastrophe.”
He soon stunned the AIDS community by announcing the formation of
a Presidential AIDS Advisory Panel populated by a handful of dissident
scientists who disputed the link between HIV and AIDS. With the
medical and scientific worlds’ attention finally turning to
South Africa and hopes running high that the raging epidemic there
could be muted, it was becoming horrifyingly clear that the country’s
leadership was embracing a policy of denial and refusal. The surreal
pronouncements of the President and his Minister of Health variously
ran: “The cause of AIDS is not known; the treatments are deadly
in themselves; and, no matter, since we can’t afford to treat
everybody, we won’t treat anybody.” Whether explained
by paranoia, Soviet science, intellectual stubbornness or cold political
calculation, Mbeki seemed entrenched. The growing activist movement,
now joined by Mandela, regretfully found itself pitted against a
government that had liberated them less than a decade before.
It’s been over three years since the Durban conference and
the world has changed in many strange ways. In developing nations,
resistance by the pharmaceutical industry has retreated, money from
the U.S. and a Global Fund has been promised to buy life for HIV-infected
Africans, pilot programs have shown that treatment works as well
as it does in rich countries, and affordable and practical combinations
of generic drugs are now available, with prices continuing to fall.
In South Africa, after years of legal challenges, demonstrations
and civil disobedience led by TAC, the government has apparently
now withdrawn its objection to saving its citizens and a plan is
being readied to make antiretroviral treatment widespread. Hopefully,
South Africans will soon be free to start the next, perhaps more
difficult phase of their struggle. Last month, as disease began
to rob him of his strength, Zackie Achmat decided to accept HIV
medicines. If the tragic farce of denial and obstruction in his
country has truly come to an end, he may soon be joined by a million
of his comrades.
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