Objective
To systematically review
the evidence on the effect of cotrimoxazole (CTX) on malaria in HIV-positive
individuals on antiretroviral therapy (ART).
Methods
Web of Science, PubMed
and MEDLINE, EMBASE, Global Health and Cochrane Library databases were searched
using terms for malaria, HIV and CTX. Studies meeting the inclusion criteria
were reviewed and assessed for bias and confounding.
Results
Six studies (in Uganda,
Kenya, Malawi, Zambia and Zimbabwe) had relevant data on the effect of CTX on
malaria in patients on ART: four were observational cohort studies (OCS) and
two were randomised controlled trials (RCTs); two were in children and one in
women only. Samples sizes ranged from 265 to 2200 patients. Four studies
compared patients on ART and CTX with patients on ART alone; 2 (RCTs) found a
significant increase in smear-positive malaria on ART alone: (IRR 32.5
CI = 8.6–275.0 and HR 2.2 CI = 1.5–3.3) and 2 (OCS)
reported fewer parasitaemia episodes on CTX and ART (OR 0.85
CI = 0.65–1.11 and 3.6% vs. 2.4% of samples P = 0.14).
One OCS found a 76% (95% CI = 63–84%) vs. 83% (95%
CI = 74–89%) reduction in malaria incidence in children on CTX and
ART vs.
on CTX only, when both were compared with HIV-negative children. The other
reported a 64% reduction in malaria incidence after adding ART to CTX
(RR = 0.36, 95% CI = 0.18–0.74). The 2 RCTs were unblinded.
Only one study reported adherence to CTX and ART, and only two controlled for
baseline CD4 count.
Conclusion
Few studies have
investigated the effect of CTX on malaria in patients on ART. Their findings
suggest that CTX is protective against malaria even among patients on ART.
Table 1
Summary of studies on the effect of CTX on malaria in HIV-infected patients on ART
| Author/year | Type of study | Study population | Main study aim | Number of participants (median follow-up) | Main study or non-malarial outcome. Ratio (95% CI) | Malaria diagnosis (number of episodes). | Malaria comparison by CTX/ART | Association between malaria and CTX. Ratio (95% CI) |
|---|---|---|---|---|---|---|---|---|
| Bwakura-Dangarembizi 201434 | RCT | Children on ART (Uganda and Zimbabwe) | Assess the effect of stopping vs. continuing CTX in children on ART | 758 (2.1 years) | Stopping CTX associated with higher rates of hospitalisation or death. HR 1.64 (1.14–2.37 P = 0.007) | Positive smear or RDT (169) | ART onlyvs. CXT/ART | HR 2.21 (1.50–3.25;P < 0.001) Median parasite density (221 vs. 153) Hospitalisation for malaria (49 vs. 21) |
| Campbell/201235 | RCT | Adults on ART (Uganda) | Assess effect of stopping CTX on malaria and diarrhoeal incidence | 836 (4 months*) | Stopping CTX associated with higher incidence of diarrhoea IRR 1.8 (1.3–2.4, P < 0.001) | Smear positive fever (57) | ART onlyvs. CXT/ART | IRR 32.5 (8.6–275.0;P < 0.001) Parasite density >1250 parasites/μl (70% vs. 100%) |
| Gasasira/201012 | Cohort | HIV-infected and uninfected children (Uganda) | Assess protective efficacy of CTX on malaria and prevalence of CTX resistance mutations in P. falciparum | 517 HIV-uninfected (2.1 years) and 292 HIV-infected (2.4 years) | Prevalence of DHFR and DHPS mutations was >90%. Efficacy of CTX on malaria (HIV infected vs. uninfected) was 80% (72–85%) | Smear positive fever (576 total, 65 in HIV positive) | Efficacy†(CTX with ART vs. HIV negative; CTX onlyvs. HIV negative) | CTX and ART: efficacy = 76% (63–84%) CTX only: efficacy = 83% (74–89%) |
| Mermin/200619 | Cohort | HIV-infected adults (Uganda) | Assess the effect of ART on malaria and additive effects of CTX, ART and ITNs. Had 4 phases; one-no intervention (NI), two-CTX, three-CTX and ART, four-CTX, ART and ITNs | Phase; one 466 (154 days), two399 (532 days),three 1035 (126 days), four989 (560 days) | Adjusted IRR Cumulative (phase one as reference) CTX vs. NI 0.24 (0.12–0.17) P < 0.001 CTX/ART/ITNs vs. NI 0.05 (0.03–0.08) P < 0.001 Additive effect (the previous phase as the reference) CTX vs. NI 0.24 (0.15–0.38) P < 0.001CTX/ART/ITNs vs. CTX/ART 0.58 (0.31–1.11) P = 0.1 | Smear positive fever smear. (166) | Cumulative CTX/ARTvs. NI Additive CTX/ARTvs. CTX | Cumulative 0.08 (0.04–0.17) P < 0.001 Additive effect 0.36 (0.18–0.74)P = 0.006 Similar rates observed when malaria defined as parasitaemia >1250 μl |
| Skinner Adams/201236 | Cohort | HIV-infected women in OCTANE trial‡ (Kenya, Uganda, Malawi, Zambia) | Assess effect of LPV/R compared to nevirapine-based ART on malaria | 265§ | Samples positive for malaria in subjects receiving LPV/R compared to those receiving NVP-based ART (2.8% vs. 1.8%, P = 0.13) | Positive smear, RDT or malaria antigen in plasma (104) | ART vs. CTX and ART only | Number of positive samples; Analysing one episode per subject 2.9%vs.. 2.2% P = 0.42 Allowing multiple episodes per subject 3.6% vs. 2.4%P = 0.14 |
| Walker/201018 | Cohort | HIV-infected adults in the DART trial¶(Ugandan sites) | Assess effect of CTX on survival, WHO stage, malaria, CD4, BMI and haematological indices after initiating ART | 2200 (4.9 years)** | Being on CTX vs. being off CTX; Mortality (0.65, 0.50–0.85) | 2362 events (Clinically 1243, microscopically 1119) | CTX/ARTvs. ART | Clinical and laboratory diagnosis OR = 0.74 (0.63–0.88) P < 0.001. When restricted to parasite positive diagnoses OR = 0.85 (0.65–1.11)P = 0.23 |
RCT, Randomised controlled trial; IRR, incidence rate ratio; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthetase; BMI, body mass index; OR, odds ratio; LPV/R, lopinavir/ritonavir; RDT, rapid diagnostic test; DART, Development of Antiretroviral Therapy; ITNs, insecticide-treated bed nets.
*Total fup time.
†Protective efficacy (1-IRR).
‡Octane (A5208) trial sites with malaria; Kericho Kenya, Lilongwe Malawi, Kampala Uganda, Lusaka Zambia.
§Prevalence in samples, no follow-up time.
¶Development of Antiretroviral Therapy trial sites with malaria; Kampala and Entebbe, Uganda.
Purchase full article at: http://goo.gl/erFXOS
By:
1London School of Hygiene and Tropical
Medicine, London, UK
2MRC/UVRI Uganda Research Unit on AIDS,
Entebbe, Uganda
Corresponding Author Ronnie Kasirye, London School
of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. E-mail:moc.oohay@eyrisakeinnor
*freely and fully available at www.tmih.com
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