HIV Infections Clinical Trial
Official title:
Effect of Long-lasting Insecticide-treated Bednets and a Point-of-use Water Purification Device on HIV Disease Progression Among ART naïve Patients in Kenya
In many areas of the world most severely affected by the HIV/AIDS pandemic, insect and
water-borne diseases such as malaria and diarrheal disease are common causes of illness and
death. In addition, diarrhea and malaria are more common and more severe among adults and
children infected with HIV. These infections may modulate the immune system, affect the
replication of the HIV virus and could result in more rapid HIV disease progression in
co-infected individuals. Access to practical, inexpensive and easy to use interventions to
prevent these diseases may be effective in delaying HIV progression.
Current Kenya government and World Health Organization guidelines recommend the use of
cotrimoxazole (trimethoprim-sulfamethoxazole [TMP/SMX]) to prevent co-infections, including
malaria. Despite the provision of TMP/SMX to HIV-infected adults, infections with malaria
and pathogens causing diarrhea remain common causes of morbidity and mortality in many
resource-limited settings. In addition, TMP/SMX may not prevent all infections with malaria
or other pathogens due to alternative mechanisms of action, antimicrobial resistance and
non-compliance due to adverse events or other reasons.
We propose a study to evaluate the impact of providing insecticide treated bednets and a
simple water filtration device on markers of HIV disease progression among a cohort of ART
naïve, HIV infected adults prescribed TMP/SMX in Kenya. In addition, we propose to evaluate
the effect of these interventions on malaria and diarrheal disease incidence and on
compliance with TMP/SMX.
Introduction and Background:
Among the estimated 22.5 million HIV infected individuals in sub-Saharan Africa, malaria and
diarrheal disease are important causes of morbidity and mortality[1]. Preventive care
packages that protect against these co-infections may result in decreased HIV associated
morbidity and may also delay HIV disease progression[2]. Long lasting insecticidal nets
(LLIN) and water purification systems may be practical and effective interventions for
reducing malaria and diarrheal disease incidence and delaying disease progression in HIV
infected individuals.
The World Health Organization currently recommends TMP/SMX prophylaxis for immunocompromised
HIV infected individuals[3]. TMP/SMX is active against a number of pathogens that cause
morbidity and mortality amongst HIV infected individuals, including malaria and infectious
causes of diarrhea[4]. Randomized clinical trials in HIV infected children and adults
demonstrate marked survival benefits with use of TMP/SMX and cotrimoxazole prophylaxis is
recommended for people with HIV in the Kenya Ministry of Health guidelines[5]. In addition,
observational studies have suggested benefit on markers of HIV disease progression[5, 6].
HIV infected individuals are at increased risk for malaria infection[7]. LLIN have been
associated with a 17% reduction in mortality and a 50% reduction in uncomplicated malaria in
areas of stable malaria transmission in HIV-uninfected adults and are a cost-effective
method of malaria prevention[8, 9]. In HIV infected individuals, TMP/SMX prophylaxis has
been shown to decrease episodes of malaria from ~50/100 person-years (p-yrs) to 9
episodes/100 p-yrs[10]. LLIN may provide additive benefit when combined with TMP/SMX in HIV
infected individuals. Amongst HIV infected individuals receiving HAART and TMP/SMX, the
addition of LLIN resulted in a 42-60% reduction in the incidence of symptomatic malaria[10].
In HIV infected children receiving TMP/SMX, LLIN were associated with marked decreases in
malarial parasitemia[11]. LLIN are simple to administer, requiring a single encounter for
long term provision of the intervention, and, in contrast to TMP/SMX, do not pose risk to
the individuals of drug toxicity or development of resistant microbial flora.
In addition to malaria, diarrheal disease remains a major cause of morbidity and mortality
amongst HIV infected individuals in many parts of sub-Saharan Africa[12, 13]. Limited access
to clean water for drinking and food preparation results in exposure to numerous bacterial,
viral and parasitic agents of diarrheal disease. Prophylaxis with TMP/SMX has been shown to
reduce diarrheal episodes in HIV infected adults from 204 to 148 per 100 person-years[6].
Among HIV-infected adults, the provision of purified drinking water resulted in a 25%
reduction in the rate of diarrhea per person year. The addition of TMP-SMX in this cohort
resulted in a 67% reduction in diarrheal episodes, suggesting an additive benefit of clean
water and TMP/SMX in reducing diarrheal incidence among HIV infected individuals[14].
Similar to LLIN, water filtration devices provide benefit by preventing host ingestion of
pathogens and are free of concerns regarding drug resistance or toxicity. Water filtration
devices may require more intensive use/training/compliance than LLIN and compliance with
daily use of these devices may reduce effectiveness.
It is important to determine if the provision of LLIN and a simple microbiological water
purification system are able to slow HIV progression and to reduce the incidence of malaria
and diarrheal disease when given in combination with TMP/SMX. If beneficial, this
combination of interventions may represent a potentially inexpensive and practical
intervention to include as part of an optimized prevention package for HIV-infected
individuals in Africa.
Justification of the Study:
Antiretroviral therapy (ART) has dramatically improved the lives of millions of individuals.
However, many HIV infected individuals do not yet meet criteria for ART initiation or have
limited access to HIV care and treatment. In addition, ART is expensive, can be difficult to
tolerate and can lead to the development of resistant virus. Identifying inexpensive,
practical and safe interventions to delay disease progression may allow HIV infected
individuals to remain healthy for longer periods before requiring ART and may reduce
morbidity and mortality due to co-infections. To our knowledge, our study will be the first
to look at the effects of non-pharmacological interventions to prevent infectious diseases
specifically as a means of delaying HIV disease progression in resource limited settings.
Procedures:
Adult men and women participating in or referred to the HIV Care and Treatment Clinics at
each of the included sites will be offered eligibility screening. HIV seropositive
individuals with a documented CD4 count ≥350 cells/mm3 will be considered potentially
eligible. Those who agree to participate, are willing and able to provide informed consent,
are WHO stage I or II based on clinical exam and history (or Stage III based on pulmonary TB
only and have completed 2 months of first-line TB therapy), are 18 years of age or older and
who are not pregnant (based on urine beta-HCG testing if female) will be offered to
participate in this study. Pregnancy testing will be performed at each study visit (every
three months) for all premenopausal women. Women who become pregnant during the course of
the study will continue to be followed.
All invited participants will be required to sign written informed consent prior to
enrollment. At enrollment, all participants will complete a standardized questionnaire
assessing medical and social history and will undergo a complete physical examination. Blood
specimens will be collected for full blood count with differential, malaria diagnostics,
TMP/SMX drug levels, measurement of absolute CD4 count and HIV RNA levels.
A detailed questionnaire will also be administered in order to assess socio-economic status,
living conditions, level of education completed, sexual behavior and occupation. This
questionnaire will also document potential exposures to infectious diseases such as water
supply, sanitation facilities, exposure to mosquitoes and use of LLIN. In addition, a
detailed clinical history will also be collected to document any prior illnesses or
treatments relevant to HIV or co-infections.
Detailed information regarding the location of each participant's current residence and any
additional residences that they consider as a primary dwelling will also be collected by
field workers at each site. Global positioning system (GPS) coordinates may be collected at
the location of each participant's site of primary residence to facilitate patient tracing.
This information will be stored as well as any other potential contact information available
(such as cell phone numbers) in order that participants may be traced for the purposes of
the study.
All enrolled participants will have scheduled three monthly study visits (enrollment, months
3, 6, 9, 12, 15, 18, 21 and 24) at the clinic from which they were enrolled. At each follow
up visit, a standardized questionnaire designed to assess any change in socio-demographic
variables or clinical history will be performed. A physical examination will also be
performed at each visit. Blood will be collected at all visits for determination of
asymptomatic malaria infection as well as markers of other infectious and non-infectious
disease markers. At the month 6, 12, 18 and 24 visit, blood will also be collected for
measurement of full blood count with differential and CD4 count. Measurement of HIV RNA will
be collected at enrolment, the 12 month visit and the 24 month visit. All blood will be
separated into plasma and PBMC's (peripheral blood mononuclear cells) and stored for future
studies. Any future study utilizing stored specimens will obtain approval from both the
Kenya Medical Research Institute and the University of Washington Ethical Review Boards.
Individuals who have evidence of clinical malaria and are parasitemic will be treated
following standard Kenyan treatment guidelines. Treatment will be provided by study funds at
the clinic according to Kenyan standard of care. Asymptomatic patients will be instructed to
return to the clinic immediately if fever develops for repeat testing. Study participants
will also be encouraged to come to the study clinic when they are sick in between scheduled
visits. During these unscheduled visits for illness, participants with clinical features of
malaria will undergo rapid diagnostic testing to confirm malaria infection. Participants who
are confirmed to have clinical malaria by rapid diagnostic testing will be referred for free
treatment as recommended by the Kenya Ministry of Health. In addition, blood will be drawn
for PCR, and malaria thick and thin smears at all unscheduled visits for fever.
Each participant will be visited at their declared residence at two randomly determined time
points per year during the course of the study period. All participants will be consented
for these visits. Participants may consent for participation without consenting for these
visits. Participants who do not consent for these visits will not undergo random home
visitation. For participants who consent to the random visitations, the field worker
visiting the participant will collect information related to the use of the bednet and water
filtration device in order to assess compliance. Information on household members recent
illness of malaria and diarrhea will be obtained at these visits.
During the course of the 24 month follow up period, some individuals are expected to meet
criteria to initiate ART based on CD4 count or clinical staging. All individuals who are
enrolled in the study and who initiate ART will provide detailed information regarding their
use of ART, adherence and tolerability. This will aid in the clinical management of these
individuals and will provide additional data regarding the response to ART in the groups.
;
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