Malaria Parasitemia and Parasite Density in Antiretroviral-Treated HIV-Infected Adults Following Discontinuation of Cotrimoxazole Prophylaxis

Abstract

Background: Cotrimoxazole (CTX) discontinuation increases malaria incidence in human immunodeficiency virus (HIV)-infected individuals. Rates, quantity, and timing of parasitemia rebound following CTX remain undefined.

Methods: Serial specimens from a trial of HIV-infected individuals receiving antiretroviral treatment (ART) randomized to continue (the CTX arm) or discontinue (the STOP-CTX arm) were examined for malaria parasites by quantitative reverse transcription polymerase chain reaction (PCR). Specimens obtained at enrollment and then quarterly for 12 months and at sick visits were assessed; multiplicity of infection was evaluated by PCR that targeted the polymorphic msp-1/msp-2 alleles.

Results: Among 500 HIV-infected adults receiving ART (median ART duration, 4.5 years), 5% had detectable parasitemia at baseline. After randomization, parasite prevalence increased over time in the STOP-CTX arm, compared with the CTX arm, with values of 4% and <1%, respectively, at month 3, 8% and 2% at month 6, 14% and 2% at month 9, and 22% and 4% at month 12 (P = .0034). The combined mean parasite density at the various time points was higher in the STOP-CTX arm (4.42 vs 3.13 log10 parasites/mL; P < .001). The parasitemia incidence was 42.0 cases per 100 person-years in the STOP-CTX arm and 9.9 cases per 100 person-years in the CTX arm, with an incidence rate ratio of 4.3 (95% confidence interval, 2.7-7.1; P < .001). After enrollment, mixed infections (multiplicity of infection, >1) were only present in the STOP-CTX arm.

Conclusion: Discontinuation of CTX by HIV-infected adults receiving ART resulted in progressive increases in malaria parasitemia prevalence and burden.

Clinical trials registration: NCT01425073.

Keywords: HIV; adults; antiretroviral treatment; cotrimoxazole; malaria; parasitemia.

Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Figures

Figure 1.

Malaria parasite point prevalence among patients continuing cotrimoxazole (CTX) therapy (the CTX arm) and those ceasing CTX therapy (the STOP-CTX arm). Black filled bars represent asymptomatic cases in the STOP-CTX arm, and striped bars represent clinical cases in the STOP-CTX arm. Open bars represents asymptomatic cases in the CTX arm. Significant difference in the overall (clinical and asymptomatic) parasitemia prevalence between the study arms were detected after enrollment. No clinical cases were detected in the CTX arm. χ2 tests were used to test for differences between study arms in parasitemia prevalence over time.

Figure 2.

Scatterplot showing malaria parasite density at enrollment, quarterly visits, and sick visits among patients continuing cotrimoxazole (CTX) therapy (the CTX arm) and those ceasing CTX therapy (the STOP-CTX arm). Data are limited to patients with parasites detected. Triangles represent the STOP-CTX arm, whereas circles represent the CTX arm. At all visits after enrollment, the STOP-CTX arm had more malaria parasite–infected subjects and a higher mean parasite density than those in the CTX arm. Differences in parasite density between arms over the follow-up period was tested using a generalized estimating equations model with identity link, independence working correlation structure, and robust standard errors to handle repeated measures within individuals. Error bars represent means with standard errors of the mean.

Figure 3.

Malaria parasitemia incidence rates by calendar month among patients continuing cotrimoxazole (CTX) therapy (the CTX arm) and those ceasing CTX therapy (the STOP-CTX arm). Stars represent new malaria parasitemia events in the STOP-CTX arm, and diamonds represent the CTX arm. The rate of new infections was higher in the STOP-CTX arm and peaked one year after the start of the study (January to March 2013) and then in August 2013 that coincided with increasing time after cessation of CTX therapy.

Figure 4.

Multiplicity of infections at enrollment, quarterly visits, and malaria sick visits among patients continuing cotrimoxazole (CTX) therapy (the CTX arm) and those ceasing CTX therapy (the STOP-CTX arm). Black bars represent the STOP-CTX arm, whereas hatched bars represent the CTX arm. After enrollment, all infections in the CTX arm were monoinfections. More mixed infections were observed in individuals who stopped CTX therapy.