HIV-1-infection Clinical Trial
Official title:
Randomized Clinical Trial to Assess Whether the Duration of Cotrimoxazole Preventive Therapy in HIV Patients With CD4 Counts >350 CD4 Cells/µL by Antiretroviral Treatment Influences the Rate of Carriage of Multidrug-resistant Bacteria
Cotrimoxazole preventive therapy (CPT) is recommended for prevention of morbidity and mortality due to Pneumocystis pneumonia and other infections in HIV positive patients with low immunity. Common clinical practice is to start CPT in any patient with CD4 counts below 200/µL, and, conversely, to stop CPT when immunity has been restored by antiretroviral treatment to CD4 counts above 200/µL or when viral suppression has been documented for 3 months. However, the latest WHO guidelines widely expands the indication for CPT by advocating for settings with high prevalence of malaria and bacterial infections, that all patients with HIV start CPT regardless of CD4 counts and clinical stage. Furthermore, WHO recommends these patients to continue CPT indefinitely regardless of evidence of immune restoration (The recommendation is for settings with high prevalence of malaria and bacterial infections, not for high-income countries). There is limited scientific evidence to recommend prolonged CPT, as studies have shown it is associated with modestly reduced morbidity due to pneumonia, meningitis and malaria, but no corresponding reduction in mortality. The impact of such a large increase in antibiotic use on the emergence of antimicrobial resistance has not been thoroughly considered. Our previous studies in Tanzania showed that multidrug-resistant bacteria frequently cause bloodstream infections with resultant very high case-fatality rates. As genes encoding for multiple antibiotic resistance traits are transferred by plasmids together with resistance towards cotrimoxazole, prolonged CPT will likely favor the selection of carriage of multidrug-resistant gut bacteria. The proposed randomized clinical trial is designed to assess whether prolonged CPT in HIV-positive patients results in increased fecal carriage of multi-drug resistant gut microbes or increased nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Secondary endpoints are morbidity (clinical events, hospitalizations) and mortality. Stool specimens, nasal swabs and clinical data will be collected from persons attending voluntary counseling and testing facilities and HIV-clinics in Dar es Salaam, Tanzania. The study results may have important impact on public health in terms of assisting development of rational recommendations for CPT use, and may help prevent emerging antibiotic resistance.
Background Bacterial infections account for a large proportion of global morbidity and
mortality. While antimicrobial drugs have helped save millions from the consequences of these
infections, emerging antimicrobial resistance now threatens to reverse those gains. The
HIV-epidemic renders large populations drastically more susceptible to bacterial infections,
particularly in Sub-Saharan Africa, where HIV is rampant and health-systems to deal with the
consequences are insufficient. Indiscriminate use of antimicrobials is thought to be the main
driving force behind emerging resistance. The opportunistic infection Pneumocystis jirovecii
pneumonia (PJP) is a major cause of mortality among HIV-infected people with low immunity.
Continuous cotrimoxazole preventive therapy (CPT) has proved to reduce morbidity and
mortality from PJP globally, as well as in Africa where the burden of HIV is largest. The
impact of this large-scale antibiotic use on emergence of antimicrobial resistance in Africa
remains unclear. In a recent literature review, Sibanda and colleagues found only two studies
specifically designed to answer the question of whether CPT induced resistance in common
bacterial pathogens, and 15 other studies that assessed the question as sub-analyses of
studies designed for other purposes. The two targeted studies both assessed resistance in
pneumococci, one finding increased resistance to clindamycin in the CPT group, neither
finding any difference in resistance to penicillin. While most of the other 15 studies
assessed penicillin-resistance in pneumococci and methicillin-resistance in Staphylococcus
aureus (MRSA), only two studies evaluated the effect on Gram-negative bacteria. Among these,
the study from San Francisco showed significantly higher temporal increase from 1988 to 1995
in resistance to cotrimoxazole, ampicillin, cefazolin and gentamicin in clinical isolates of
E. coli from HIV-positives than from HIV-negatives. The study of HIV-infected children with
pneumonia in Cape Town did not find any association between CPT and resistance in clinical
isolates, including 26 isolates of Klebsiella pneumonia, the most prevalent Gram-negative
microbe in this study. In previous research in Tanzania, we found that multi-drug resistance
in Gram-negative bacteria is prevalent and a problem of major public health concern, as
invasive infections with such bacteria was associated with a large increase in mortality. Our
study found case-fatality rates (>70%) approaching those of the pre-antibiotic era in
systemic bacterial infections with multi-resistant Gram-negative bacteria harboring
extended-spectrum beta-lactamase (ESBL) resistance. ESBLs are enzymes that render the
all-important antibiotics, penicillins and cephalosporins, useless. We also confirmed
previous findings that case-fatality rates from bacterial sepsis was higher in HIV-infected
than HIV-negative patients. Most disturbingly, our study confirmed that in
multidrug-resistant Gram-negative bacteria the gene encoding for ESBL resistance was
transferred by plasmids together with resistance to several other antibiotics, including
cotrimoxazole. Thus, it is plausible that widespread cotrimoxazole use could lead to
selection of multidrug-resistant Gram-negative bacteria in the gut of HIV-patients, which
consequently could contribute to the rapid spread of these harmful and difficult-to-treat
bacteria. In high-resource countries, it has been shown that CPT can safely be discontinued
when CD4 counts increase beyond 200/uL. Recent studies from Sub-Saharan Africa indicate that
prolonged CPT after immune restoration to CD4 counts > 200/µL by antiretroviral treatment
(ART) may be beneficial as it is associated with reduced hospitalization from malaria and
bacterial infections in children. There was, however, no difference in mortality among those
who stopped and continued CPT. In the "2014 supplement to the WHO guidelines on the use of
antiretroviral drugs for treating and preventing HIV infection", the recommendation for CPT
use is widely expanded for settings with high prevalence of malaria and bacterial infections,
where it is recommended that all patients with HIV start CPT regardless of CD4 counts and
clinical stage and receive prolonged CPT for indefinitely time. Tanzanian national guidelines
recommend discontinuing CPT when patients are stabilized with CD4 counts >350/µL, which is a
more extensive recommendation than European guidelines, but much less extensive than the WHO
recommendations for "settings with high prevalence of malaria and bacterial infections".
Cotrimoxazole has been widely used for a number of different indications and, as a result,
cotrimoxazole resistance in general has increased. Given the limited published data on these
important public health issues, we designed this study to address the potential impact of
prolonged CPT on antimicrobial resistance development with particular focus on Gram-negative
gut microbes, VRE (vancomycin-resistant enterococci), and nasal carriage of MRSA. If the
study should confirm a marked increase in carriage of multidrug-resistant bacteria in
patients on prolonged CPT this needs to be considered when developing new guidelines. We also
aim at assessing whether restoration of immunity by ART could be a way to counteract this
threat of antimicrobial resistance. This proposed randomized clinical trial will be performed
in the setting of the ongoing Dar es Salaam - Bergen collaborative initiative and will
include local investigators and laboratory workers, along with Norwegian investigators with
scientific experience from clinical and molecular studies in Tanzania.
Problem statement/ research gap CPT has been standard of care for preventing PJP and other
infections among HIV-infected patients with CD4 counts < 200µL since the early 1990s. The
recent recommendation by WHO to give CPT indefinitely to HIV-infected people in
resource-constrained settings, even to those with initial good immunity (CD4 counts above
350/µL) and to those whose immunity has been restored by antiretroviral treatment, would lead
to a massive increase in cotrimoxazole consumption in Sub-Saharan Africa, which has the
largest burden of HIV-infection. While this recommendation is based on limited scientific
data regarding short-term morbidity, there is no evidence of improved survival and the
potential harmful implication for selection of multidrug-resistant bacteria in HIV-patients
on prolonged CPT has not been comprehensively studied.
Rationale of the study Continuing CPT indefinitely stable good immunity with CD4 counts
>350/µL has been shown to reduce morbidity, but not mortality, in persons living with HIV in
resource-constrained settings. Complying with recommendation for continuation of CPT
indefinitely in patients with restored immunity and virological control would imply a
massively increased consumption of cotrimoxazole in HIV-endemic countries. The risk of
increased carriage of multidrug-resistant bacteria among HIV-patients on prolonged CPT has
not been comprehensively studied, but has potentially grave implications for public health,
since systemic infections with these resistant bacteria are very difficult to treat and
associated with very high mortality rates. The current study is designed to assess whether
prolonged CPT is associated with increased carriage of multidrug-resistant bacteria. The
results of this study may have important implications for development of new guidelines on
CPT use for resource-constrained settings and may help preventing emerging antibacterial
resistance.
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