Malaria returns when Ugandan ART patients stop cotrimoxazole

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Ugandans with HIV infection receiving antiretroviral therapy who discontinued cotrimoxazole prophylaxis in a randomised study had a 28-fold higher risk of developing malaria when compared with those who continued taking cotrimoxazole, researchers from the US Centers for Disease Control reported this week at the 2008 HIV Implementers’ Meeting in Kampala, Uganda.

Cotrimoxazole is an antibiotic recommended for all HIV-positive people in resource-limited settings with high HIV prevalence.

It has been shown to reduce the risk of serious bacterial infections and, in people with CD4 cell counts below 200 cells/mm3, it protects against the development of Pneumocystis pneumonia (PCP), a leading cause of death in people with advanced HIV disease.

Glossary

malaria

A serious disease caused by a parasite that commonly infects a certain type of mosquito which feeds on humans. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness. 

diarrhoea

Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.

smear

A specimen of tissue or other material taken from part of the body and smeared onto a microscope slide for examination. A Pap smear is a specimen of material scraped from the cervix (neck of the uterus) examined for precancerous changes.

Pneumocystis carinii pneumonia (PCP)

Pneumocystis carinii pneumonia is a form of pneumonia that is an AIDS defining illness.

data safety monitoring board (DSMB)

An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC).

Another study in Uganda has shown that cotrimoxazole reduced the risk of death by 25% in people not receiving antiretroviral therapy.

Cotrimoxazole also has a protective effect against malaria.

Cotrimoxazole is given routinely to all patients in the Home Based AIDS Care cohort, a study of the delivery of HIV treatment, prevention and care among 1,000 families in rural Uganda coordinated by CDC-Uganda.

However the long-term clinical value and cost-effectiveness of giving cotrimoxazole to people on antiretroviral therapy with CD4 cell counts above 200 cells/mm3 in resource-limited settings with a high malarial burden is unknown. In the developed world, cotrimoxazole prophylaxis is usually discontinued when the CD4 cell count rises above 200 cells/mm3.

The HBAC study team designed a randomized trial to test whether stopping cotrimoxazole prophylaxis would be safe. The study randomised 836 patients who had had CD4 cell counts above 200 cells/mm3 either to discontinue prophylaxis (384 persons) or stay on it indefinitely (452 persons).

The average CD4 cell count of participants was 505 and 476 cells/mm3 in the on and off-treatment arms respectively, all participants had undetectable viral load, and had been on antiretroviral treatment for an average of 3.68 years.

The study was planned to last two years, but was stopped by its Data Safety Monitoring Board after just 118 days due to the very substantial difference in outcome that had already emerged.

After 118 days the off-treatment group had experienced 228 malarial episodes compared with 87 in the on-treatment group (40% vs. 15% of participants experiencing an episode), and the rate of positive smear diagnosis of malaria (the study’s primary endpoint) was 12.3% in the off-treatment arm and 0.4% in the on-treatment arm.

When the relative risk of smear-positive malaria was calculated, those who stopped cotrimoxazole were found to be at 28-fold higher risk of developing malaria when compared to those who continued cotrimoxazole treatment.

The study also evaluated the incidence of diarrhoea (defined as three loose stools in a 24-hour period). A small but statistically significant increase was seen in the off-treatment group, who had a 1.8-fold higher risk of diarrhoea (95% confidence interval 1.3 - 2.3, p<0.0001).

The incidence of malaria was almost ten times higher than the peak incidence seen during previous months of the HBAC study, leading some to question whether the elevated risk seen in this study was similar to the rebound effect seen in people who leave a malarial setting and later return, having lost a degree of immunity.

Presenting the results, James Campbell of CDC-Uganda said: “We don’t know whether the exaggerated incidence is due to a rebound effect - as in the case of intermittent therapy in infants.”

The study is unable to determine whether the incidence of malaria reported is similar to the background level in the general population. Professor Charles Gilks of the World Health Organization, chairing the conference session, pointed out that 10% of all adults in Entebbe, Uganda, was found to have slide-positive malaria, and the risk increased in HIV-positive people as the CD4 cell count fell.

James Campbell said that the ability of the study to answer some key questions had been limited due to the swift termination of the study. In particular, he said, it was impossible to judge from the findings whether the benefit of protection from malaria and diarrhoea is outweighed in the long-term by the cost of the drugs and the risk of malarial resistance to cotrimoxazole.

The study is also unable to provide information on the effect of repeated episodes of malaria on the long-term outcomes of people with high CD4 cell counts on antiretroviral therapy.

References

Campbell J, Tappero J, et al. HIV-infected Ugandans on HAART with CD4 cell counts over 200 cells/mm3 who discontinue cotrimoxazole have increased risk of malaria and diarrhea. 2008 HIV Implementers’ Meeting, Kampala, Uganda, abstract number unlisted.