Longitudinal effect of CD4 by cotrimoxazole use on malaria incidence among HIV-infected Ugandan adults on antiretroviral therapy: a randomized controlled study.

BACKGROUND: The effect of CD4 count on malaria incidence in HIV infected adults on antiretroviral therapy (ART) was assessed in the context of a randomized controlled trial on the effect of stopping cotrimoxazole (CTX). METHODS: This study presents a sub-analysis of the COSTOP trial (ISRCTN44723643) which was carried out among HIV-infected Ugandan adults stable on ART with CD4 counts ≥250 cells/µl. Participants were randomized (1:1) to continue CTX or stop CTX and receive matching placebo, and were followed up for a minimum of 1 year (median 2.5 years). CD4 counts were measured at baseline, 3 months and then every 6 months. Clinical malaria was defined as fever and a positive blood slide. First, the relationship between current CD4 count during follow-up and malaria among participants on placebo was examined; using random effects Poisson regression to account for repeated episodes. Second, the effect of CD4 count at enrolment, CD4 count at ART initiation, and CD4 count during follow-up on malaria, was assessed within each trial arm; to examine whether the effect of CD4 count differed by CTX use. RESULTS: 2180 participants were enrolled into the COSTOP trial. The incidence of clinical malaria was approximately four episodes/100 person years in the CTX arm and 14 episodes/100 person years in the placebo arm. There was no evidence of an association of current CD4 and clinical malaria incidence (P = 0.56), or parasitaemia levels (P = 0.24), in the placebo arm. Malaria incidence did not differ by CD4 count at ART initiation, enrolment or during follow up, irrespective of CTX use. When compared with participants in the lowest CD4 stratum, rate ratios within each trial arm were all close to 1, and P values were all above P = 0.30. CONCLUSIONS: The immune status of HIV infected participants who are stable on ART as measured by CD4 count was not associated with malaria incidence and did not modify the effect of stopping CTX on malaria. The decision of whether to stop or continue CTX prophylaxis for malaria in HIV infected individuals who are stable on ART should not be based on CD4 counts alone. COSTOP trial registration number ISRCTN44723643

Incidence of malaria by cotrimoxazole use in HIV-infected Ugandan adults on antiretroviral therapy: a randomised, placebo-controlled study.

INTRODUCTION: Previous unblinded trials have shown increased malaria among HIV-infected adults on antiretroviral therapy (ART) who stop cotrimoxazole (CTX) prophylaxis. We investigated the effect of stopping CTX on malaria in HIV-infected adults on ART in a double-blind, placebo-controlled trial. METHODS: HIV-infected Ugandan adults stable on ART and CTX with CD4 cell count at least 250 cells/μl were randomized (1 : 1) to continue CTX or stop CTX and receive matching placebo (COSTOP trial; ISRCTN44723643). Clinical malaria was defined as fever and a positive blood slide, and considered severe if a participant had at least one clinical or laboratory feature of severity or was admitted to hospital. Malaria incidence and rate ratios were estimated using random effects Poisson regression, accounting for multiple episodes. RESULTS: A total of 2180 participants were enrolled and followed for a median of 2.5 years; 453 malaria episodes were recorded. Malaria incidence was 9.1/100 person-years (pyrs) [95% confidence interval (CI) = 8.2-10.1] and was higher on placebo (rate ratio 3.47; CI = 2.74-4.39). Malaria in the placebo arm decreased over time; although incidence remained higher than in the CTX arm, the difference between arms reduced slightly (interaction P value = 0.10). Fifteen participants experienced severe malaria (<1%); overall incidence was 0.30/100 pyrs (CI = 0.18-0.49). There was one malaria-related death (CTX arm). CONCLUSION: HIV-infected adults - who are stable on ART and stop prophylactic CTX - experience more malaria than those that continue, but this difference is less than has been reported in previous trials. Few participants had severe malaria. Further research might be useful in identifying groups that can safely stop CTX prophylaxis

Effect of antiretroviral therapy on malaria incidence in HIV-infected Ugandan adults.

INTRODUCTION: Using the data of a trial on cotrimoxazole (CTX) cessation, we investigated the effect of different antiretroviral therapy (ART) regimens on the incidence of clinical malaria. METHODS: During the cotrimoxazole cessation trial (ISRCTN44723643), HIV-infected Ugandan adults with CD4 at least 250 cells/μl were randomized to receive either CTX prophylaxis or placebo and were followed for a median of 2.5 years. Blood slides for malaria microscopy were examined at scheduled visits and at unscheduled visits when the participant felt unwell. CD4 cell counts were done 6-monthly. Malaria was defined as fever with a positive blood slide. ART regimens were categorized as nucleoside reverse transcriptase inhibitor (NRTI) only, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or protease inhibitor containing. Malaria incidence was calculated using random effects Poisson regression to account for clustering of events. RESULTS: Malaria incidence in the three ART regimen groups was 9.9 (3.6-27.4), 9.3 (8.3-10.4), and 3.5 (1.6-7.6) per 100 person-years, respectively. Incidence on protease inhibitors was lower than that on the other regimens with the results just reaching significance (adjusted rate ratio 0.4, 95% confidence interval = 0.2-1.0, comparing with NNRTI regimens). Stratification by CTX/placebo use gave similar results, without evidence of an interaction between the effects of CTX/placebo use and ART regimen. There was no evidence of an interaction between ART regimen and CD4 cell count. CONCLUSION: There was some evidence that protease inhibitor-containing ART regimens may be associated with a lower clinical malaria incidence compared with other regimens. This effect was not modified by CTX use or CD4 cell count. The antimalarial properties of protease inhibitors may have clinical and public health importance

Exit interviews administered to patients participating in the COSTOP placebo controlled randomised trial in Uganda.

INTRODUCTION: COSTOP was a randomised controlled trial designed to assess the risks and benefits to HIV-infected participants stabilised on anti-retroviral treatment of stopping cotrimoxazole (CTX). In order to assess the extent to which patients may have had access to and used CTX other than that supplied as study drug it was decided to conduct an exit interview. METHODS: A structured interview was administered by interviewers who were not associated with the COSTOP trial team in order to make it easier for participants to respond truthfully to sensitive questions about adherence to the study protocol. RESULTS: A total of 1993 participants were interviewed. Only 29 (1.7%) said they had taken their left over CTX; 101 (6.1%) had kept supplies at home. When asked about obtaining open label CTX during the trial 92 (4.7%) participants said they had done so, in contrast to only 12 who admitted doing so when asked at trial visits. The questions participants found most difficult to answer honestly at clinic visits were those concerning adherence to trial drugs (15.6% of participants) and whether they had slept under the insecticide treated mosquito nets (14.9%). DISCUSSION: The exit interview demonstrated that there was some evidence of open label drug being taken by the participants. However, the results from the interview do not suggest that the trial results would have been seriously compromised. We would recommend the exit interview as a valuable way of assessing adherence to trial procedures

Malaria parasitemia among blood donors in Uganda

Background: Malaria remains a leading transfusion associated infectious risk in endemic areas. However, the prevalence of malaria parasitemia has not been well characterized in blood donor populations. This study sought to determine the prevalence of Plasmodium in red blood cell (RBC) and whole blood (WB) units after the rainy season in Uganda. Methods and materials: Between May and July 2018, blood was collected from the sample diversion pouch of 1000 WB donors in Kampala and Jinja, Uganda. The RBC pellet from ethylenediamine tetraacetic acid (EDTA) anticoagulated blood was stored at -80°C until testing. DNA was extracted and nested PCR was used to screen samples at the genus level for Plasmodium, with positive samples further tested for species identification. Results: Malaria parasitemia among asymptomatic, eligible blood donors in two regions of Uganda was 15.4%; 87.7% (135/154) of infections were with P. falciparum, while P. malariae and P. ovale were also detected. There were 4.3% of blood donors who had mixed infection with multiple species. Older donors (>30 years vs. 17-19 years; aPR = 0.31 [95% CI = 0.17-0.58]), females (aPR = 0.60 [95% CI = 0.42-0.87]), repeat donors (aPR = 0.44 [95% CI = 0.27-0.72]) and those donating near the capital city of Kampala versus rural Jinja region (aPR = 0.49 [95% CI = 0.34-0.69]) had a lower prevalence of malaria parasitemia. Conclusions: A high proportion of asymptomatic blood donors residing in a malaria endemic region demonstrate evidence of parasitemia at time of donation. Further research is needed to quantify the risk and associated burden of transfusion-transmitted malaria (TTM) in order to inform strategies to prevent TTM

Re-engagement in HIV care following a missed visit in rural Uganda

Abstract Objective We conducted a retrospective cohort study to assess the effect of tracking People Living with HIV (PLHIV) after missed clinic visits and factors associated with return to care in rural Uganda. We assessed retention in care among 650 HIV-infected women and men. We used univariable and multivariable generalized linear models to assess demographic and self-reported factors associated with re-engagement in HIV care. Results Of 381 PLHIV who ever missed a scheduled appointment, 68% were female and most (80%) had initiated ART. Most (70%) of those tracked returned to care. Relative to men, women (adjusted risk ratio [ARR] 1.23; 95% confidence interval (CI) 1.05–1.43; p = 0.009) were more likely to return to care after active tracking. PLHIV who missed scheduled visits for other reasons (forgetting, adequate drug supplies, or long distance to clinic) had reduced odds of return to care (ARR 0.41; 95% CI 0.28–0.59; p < 0.001). These data support close monitoring of patient retention in HIV care and active measures to re-engage those who miss an appointment. Furthermore, they highlight the need for targeted interventions to those more resistant to re-engagement such as men

Re-engagement in HIV care following a missed visit in rural Uganda

Abstract Objective We conducted a retrospective cohort study to assess the effect of tracking People Living with HIV (PLHIV) after missed clinic visits and factors associated with return to care in rural Uganda. We assessed retention in care among 650 HIV-infected women and men. We used univariable and multivariable generalized linear models to assess demographic and self-reported factors associated with re-engagement in HIV care. Results Of 381 PLHIV who ever missed a scheduled appointment, 68% were female and most (80%) had initiated ART. Most (70%) of those tracked returned to care. Relative to men, women (adjusted risk ratio [ARR] 1.23; 95% confidence interval (CI) 1.05–1.43; p = 0.009) were more likely to return to care after active tracking. PLHIV who missed scheduled visits for other reasons (forgetting, adequate drug supplies, or long distance to clinic) had reduced odds of return to care (ARR 0.41; 95% CI 0.28–0.59; p < 0.001). These data support close monitoring of patient retention in HIV care and active measures to re-engage those who miss an appointment. Furthermore, they highlight the need for targeted interventions to those more resistant to re-engagement such as men

Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA)

Background: Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa. Methods: After 24 weeks of lopinavir/ritonavir-containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPImono maintenance (SARA trial; ISRCTN53817258). Joint primary end points were CD4 T-cell changes 24 weeks later and serious adverse events (SAEs); retrospectively assayed viral load (VL) was a secondary end point. Analyses were intention-to-treat. Results: A total of 192 participants were randomized to CT (n=95) or bPImono (n=97) and followed for median 60 weeks (IQR 45-84). Participants received median 4.0 years (IQR 3.5-4.4) first-line ART. Median CD4 T-cell count at first-line failure was 86 cells/mm (47-136), increasing to 245 cells/mm (173-325) after 24-week induction when 77% had V