Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active anti-retroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole.
Methods
Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6.
Results
A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3–4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3–4 anaemia (9.6/100 PY) and no cases of grade 3–4 thrombocytopenia. Of the 118 patients with grade 3–4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3–4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm3 (IQR +150;+896).
Conclusions
At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3–4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3–4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.
HuëtC., AnglaretX., ToureS., CombeP., GourvellecG., KoffiJ., N'Dri-YomanT., DabisF., & SalamonR.Incidence and risk factors of neutropenia in HIV-1 infected patients under cotrimoxazole prophylaxis.13th International AIDS Conference. 9–14 July 2000, Durban, South Africa. Abstract TuPeC3393.
3.
MooreR.D., FortgangI., KerulyJ., & ChaissonR.E.Adverse events from drug therapy for human immunodeficiency virus disease.American Journal of Medicine1996; 101: 34–40.
MoyleG., SawyerW., LawM., AminJ., & HillA.Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: a meta-analysis of six prospective, randomized, comparative studies.Clinical Therapeutics2004; 26: 92–97.
6.
MooreD.A., BenepalT., PortsmouthS., GillJ., & GazzardB.G.Etiology and natural history of neutropenia in human immunodeficiency virus disease: a prospective study.Clinical Infectious Diseases2001; 32: 469–475.
7.
DanelC., MohR., SorhoS., AnzianA., AboY., ChenalH., KangaC., EholiéS., SauvageotD., GabillardD., RouetF., BissagneneE., AnglaretX., & SalamonR.Progress report on a structured treatment interruption trial: Trivacan ANRS 1269 trial, Abidjan, Côte d'Ivoire.15th International AIDS Conference. 11–16 July 2004, Bangkok, Thailand. Abstract WeOrB1284.
8.
RouetF., EkoueviD.K., ChaixM.L., BurgardM., InwoleyA., TonyT.D., DanelC., AnglaretX., LeroyV., MsellatiP., DabisF., & RouziouxC. for the ANRS Côte d'Ivoire PAC-CI Program. Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting.Journal of Clinical Microbiology2005; 43: 2709–2717.
9.
LandmanR., SchiemannR., ThiamS., VrayM., CanestriA., MboupS., KaneC.T., DelaporteE., SowP.S., FayeM.A., GueyeM., PeytavinG., DalbanC., GirardP.M., & NdoyeI.Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal.AIDS2003; 17: 1017–1022.
10.
LaurentC., KouanfackC., Koulla-ShiroS., NkoueN., BourgeoisA., CalmyA., LactuockB., NzeusseuV., MougnutouR., PeytavinG., LiegeoisF., NerrienetE., TardyM., PeetersM., Andrieux-MeyerI., ZekengL., KazatchkineM., Mpoudi-NgoleE., & DelaporteE.Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial.Lancet2004; 364: 29–34.
JackC., LallooU., KarimQ.A., KarimS.A., El-SadrW., CassolS., & FriedlandG.A pilot study of once-daily antiretroviral therapy integrated with tuberculosis directly observed therapy in a resource-limited setting.Journal of Acquired Immune Deficiency Syndromes2004; 36: 929–934.
14.
WeidleP., MalambaS., MwebazeR., SoziC., RukundoG., DowningR., HansonD., OcholaD., MugyenyiP., MerminJ., SambB., & LackritzE.Assessement of a pilot antiretroviral drug therapy programme in Uganda: patients’ response, survival, and drug resistance.Lancet2002; 360: 34–40.
15.
BadriM., WilsonD., & WoodR.Effect of highly active anti-retroviral therapy on incidence of tuberculosis in South Africa: a cohort study.Lancet2002; 359: 2059–2064.
16.
LivesleyN., & MorrisC.Antiretroviral therapy in a primary care clinic in rural South Africa.AIDS2003; 17: 2005–2006.
17.
BadriM., BekkerL.G., OrrellC., PittJ., CilliersF., & WoodR.Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines.AIDS2004; 18: 1159–1168.
18.
OrrellC., BangsbergD.R., BadriM., & WoodR.Adherence is not a barrier to successful antiretroviral therapy in South Africa.AIDS2003; 17: 1369–1375.
19.
CoetzeeD., HildebrandK., BoulleA., MaartensG., LouisF., LabatalaV., ReuterH., NtwanaN., & GoemaereE.Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa.AIDS2004; 18: 887–895.
20.
AnglaretX., CheneG., AttiaA., ToureS., LafontS., CombeP., ManlanK., N'Dri-YomanT., & SalamonR.Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group.Lancet1999; 353: 1463–1468.
21.
WiktorS.Z., Sassan-MorokroM., GrantA.D., AbouyaL., KaronJ.M., MauriceC., DjomandG., AckahA., DomouaK., KadioA., YapiA., CombeP., TossouO., RoelsT.H., LackritzE.M., CoulibalyD., De CockK.M., CoulibalyI.M., & GreenbergA.E.Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial.Lancet1999; 353: 1469–1475.
22.
MerminJ., LuleJ., EkwaruJ.P., MalambaS., DowningR., RansomR., KaharuzaF., CulverD., KizitoF., BunnellR., KigoziA., NakanjakoD., WafulaW., & QuickR.Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda.Lancet2004; 364: 1428–1434.
23.
MaynartM., LievreL., SowP., KonyS., GueyeN., BasseneE., MetroA., NdoyeI., BaD., CoulaudJ., & CostagliolaD.Primary prevention with cotrimoxazole for HIV-1-infected adults: results of the pilot study in Dakar, Senegal.Journal of Acquired Immune Deficiency Syndromes2001; 26: 130–136.
24.
MoyleG.Anaemia in persons with HIV infection: prognostic marker and contributor to morbidity.AIDS Reviews2002; 4: 13–20.
25.
RichmanD.D., FischlM.A., GriecoM.H., GottliebM.S., VolberdingP.A., LaskinO.L., LeedomJ.M., GroopmanJ.E., MildvanD., & HirschM.S.The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial.New England Journal of Medicine1987; 317: 192–197.
26.
GelmonK., MontanerJ.S., FanningM., SmithJ.R., FalutzJ., TsoukasC., GillJ., WellsG., O'ShaughnessyM., WainbergM., & ReudyJ.Nature, time course and dose dependence of zidovudine-related side effects: results from the Multicenter Canadian Azidothymidine Trial.AIDS1989; 3: 555–561.
27.
RubinR.H., & SwartzM.N.Trimethoprim-sulfamethoxazole.New England Journal of Medicine1980; 303: 426–432.
28.
HughesW.T., LaFonS.W., ScottJ.D., & MasurH.Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia.Journal of Infectious Diseases1995; 171: 1295–1301.
29.
SullivanP.S., HansonD.L., ChuS.Y., JonesJ.L., & WardJ.W.Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: results from the multistate adult and adolescent spectrum of HIV disease surveillance project.Blood1998; 91: 301–308.
30.
FreundY.R., DousmanL., MacGregorJ.T., & MohagheghpourN.Oral treatment with trimethoprim-sulfamethoxazole and zidovudine suppresses murine accessory cell-dependent immune responses.Toxicological Sciences2000; 55: 335–342.
31.
ReislerR.B., HanC., BurmanW.J., TedaldiE.M., & NeatonJ.D.Grade 4 events are as important as AIDS events in the era of HAART.Journal of Acquired Immune Deficiency Syndromes2003; 34: 379–386.
32.
SpruanceS.L., PaviaA.T., PetersonD., BerryA., PollardR., PattersonT.F., FrankI., RemickS.C., ThompsonM., MacArthurR.D., MoreyG.E., Ramirez-RondaC.H., BernsteinB.M., SweetD.E., CraneL., PetersonE.A., PachuckiC.T., GreenS.L., BrandJ., RiosA., DunkleL.M., CrossA., BrownM.J., IngrahamP., GugliottiR., SchindzielorzA.H., & SmaldoneL.Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.Annals of Internal Medicine1994; 120: 360–368.
33.
ShaperA.G., & LewisP.Genetic neutropenia in people of African origin.Lancet1971; 2: 1021–1023.
34.
RezvaniK., FlanaganA.M., SarmaU., ConstantinoviciN., & BainB.J.Investigation of ethnic neutropenia by assessment of bone marrow colony-forming cells.Acta Haematologica2001; 105: 32–37.
35.
JacobsonM.A., GundackerH., HughesM., FischlM., & VolberdingP.Zidovudine side effects as reported by black, Hispanic, and white/non-Hispanic patients with early HIV disease: combined analysis of two multicenter placebo-controlled trials.Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology1996; 11: 45–52.
36.
ChattonJ.A.M., ChaveJ.P., SteinhauslinF., Roch-RamelF., GlauserM., & BiollazJ.Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide.British Journal of Clinical Pharmacology1992; 34: 551–554.
37.
BenowitzN.L., Perez-StableE.J., FongI., ModinG., HerreraB., & JacobP.3rd. Ethnic differences in N-glucuronidation of nicotine and cotinine.Journal of Pharmacology & Experimental Therapeutics1999; 291: 1196–1203.
38.
MeynardJ.L., GuiguetM., ArsacS., FrottierJ., & MeyohasM.C.Frequency and risk factors of infectious complications in neutropenic patients infected with HIV.AIDS1997; 11: 995–998.
39.
Majluf-CruzA., Luna-CastanosG., Trevino-PerezS., SantoscoyM., & Nieto-CisnerosL.Lamivudine-induced pure red cell aplasia.American Journal of Hematology2000; 65: 189–191.
40.
PludaJ., CooleyT., MontanerJ., ShayL., ReinhalterN., WarthanS., RuedyJ., HirstH., VicaryC., QuinnJ., YuenG.J., WainberM.A., RubinM., & YarchoanR.A phase I/II study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection.Journal of Infectious Diseases1995; 171: 1438–1447.
41.
MooreK.H., YuenG.J., RaaschR.H., EronJ.J., MartinD., MydlowP.K., & HusseyE.K.Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.Clinical Pharmacology & Therapeutics1996; 59: 550–558.
42.
ReinkeC.M., ThomasJ.K., & GravesA.H.Apparent hemolysis in an AIDS patient receiving trimethoprim/sulfamethoxazole: case report and literature review.Journal of Pharmacy Technology1996; 11: 256–362; quiz 93–95.
43.
ZonL.I., ArkinC., & GroopmanJ.E.Haematologic manifestations of the human immune deficiency virus (HIV).British Journal of Haematology1987; 66: 251–256.
44.
ShaunakS., & BartlettJ.A.Zidovudine-induced neutropenia: are we too cautious?Lancet1989; 2: 91–92.
45.
MooreR.D., & ForneyD.Anemia in HIV-infected patients receiving highly active antiretroviral therapy.Journal of Acquired Immune Deficiency Syndromes2002; 29: 54–57.
