A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/µL.

BACKGROUND: Optimal treatment of human immunodeficiency virus (HIV)-associated tuberculosis in patients with high CD4⁺ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression. METHODS: We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/µL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4⁺ T-cell counts of < 250 cells/µL, AIDS, or death. RESULTS: Intervention and comparison arms had similar median CD4⁺ counts (517 and 534 cells/µL, respectively) and HIV RNA levels (4.6 and 4.7 log10 copies/µL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis. CONCLUSIONS: Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4⁺T-cell counts of >350 cells/µL was safe and associated with clinical benefits.

Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention.

OBJECTIVES: Voluntary counseling and testing (VCT) for the human immunodeficiency virus (HIV) is recommended for persons treated for tuberculosis (TB). Opportunities to diagnose HIV may be missed by limiting HIV testing to only persons diagnosed with TB. Among TB suspects in Uganda, we determined HIV prevalence, risk behaviors, and willingness to refer family for VCT. METHODS: Consenting adult patients presenting for evaluation at a referral TB clinic received same-day VCT. TB diagnosis data were abstracted from clinical records. RESULTS: Among 665 eligible patients, 565 (85%) consented to VCT. Among these, 238 (42%) were HIV-positive. Of the HIV-infected patients, 37% had received a non-TB diagnosis. HIV seroprevalence was higher in patients with a non-TB diagnosis (49%) than those diagnosed with TB (39%) (P = 0.02). Fewer than 6% of HIV-infected patients reported always using condoms with sexual partners. The majority of patients (86%) reported being 'very willing' to refer family members for VCT. CONCLUSIONS: Over 35% of HIV-infected cases in our population would have been undetected if HIV testing was limited to cases with diagnosed TB. The high HIV seroprevalence in both TB and non-TB cases merits HIV testing for all patients evaluated at TB clinics. HIV-infected TB suspects reporting high-risk behavior are at risk for HIV transmission, and should receive risk-reduction counseling.

Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

OBJECTIVE: To evaluate the early bactericidal activity (EBA) of the new fluoroquinolones levofloxacin, gatifloxacin and moxifloxacin in patients with pulmonary tuberculosis (PTB). DESIGN: Randomized, open-label trial. Forty adults with newly diagnosed smear-positive PTB (10 per arm) were assigned to receive isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. Sputum for quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (EBA 0-2) and last 5 days of monotherapy (extended EBA, EBA 2-7). Laboratory staff were blinded to treatment assignment. RESULTS: The EBA 0-2 of INH (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day) (P = 0.14). Bactericidal activity between days 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison, the EBA 2-7 of the fluoroquinolones was greater than for INH. CONCLUSION: Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA. These drugs warrant further study in the treatment of drug-susceptible TB.

Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population.

OBJECTIVE: To examine the relationship between adherence, viral suppression and antiretroviral resistance in HIV-infected homeless and marginally housed people on protease inhibitor (PI) therapy. DESIGN AND SETTING: A cross-sectional analysis of subjects in an observational prospective cohort systematically sampled from free meal lines, homeless shelters and low-income, single-room occupancy (SRO) hotels. PARTICIPANTS: Thirty-four HIV-infected people with a median of 12 months of PI therapy. MAIN OUTCOMES: Adherence measured by periodic unannounced pill counts, electronic medication monitoring, and self-report; HIV RNA viral load; and HIV-1 genotypic changes associated with drug resistance. RESULTS: Median adherence was 89, 73, and 67% by self-report, pill count, and electronic medication monitor, respectively. Thirty-eight per cent of the population had over 90% adherence by pill count. Depending on the measure, adherence explained 36-65% of the variation in concurrent HIV RNA levels. The three adherence measures were closely related. Of 20 genotyped patients who received a new reverse transcriptase inhibitor (RTI) when starting a PI, three had primary protease gene substitutions. Of 12 genotyped patients who received a PI without a new RTI, six had primary protease gene substitutions (P < 0.03). CONCLUSION: A substantial proportion of homeless and marginally housed individuals had good adherence to PI therapy. A strong relationship was found between independent methods of measuring adherence and concurrent viral suppression. PI resistance was more closely related to the failure to change RTI when starting a PI than to the level of adherence.

Differences in time from HIV seroconversion to CD4+ lymphocyte end-points and AIDS in cohorts of homosexual men.

OBJECTIVE: To evaluate the decline in CD4+ counts in relation to the incidence of AIDS in different cohorts of homosexual men and to quantify possible consequences of laboratory variation in CD4+ measurement. METHODS: Our study includes 403 men with well documented dates of HIV seroconversion originating from five cohort studies among homosexual men. Differences in time from HIV seroconversion to the first CD4+ count dropping < 500 or 200 x 10(6)/l and to AIDS were evaluated using Kaplan-Meier survival analyses. RESULTS: We found considerable differences between cohorts in CD4+ depletion, but not in the incidence of AIDS (1987 definition). CONCLUSIONS: Variation in CD4+ depletion appears to be mainly the result of laboratory differences. Policy recommendations on a basis of CD4+ counts probably requires a calibration of measurement. The 1993 AIDS case definition leads to a site-specific shortening of the incubation time, which complicates the study of the natural history of HIV infection and of trends in the AIDS epidemic.

Modeling the impact of modified directly observed antiretroviral therapy on HIV suppression and resistance, disease progression, and death.

A simulation model that used Markov assumptions with Monte Carlo uncertainty analysis was evaluated 1500 times at 10,000 iterations. Modified directly observed therapy (MDOT) for human immunodeficiency virus was assumed to improve adherence to therapy to 90% of prescribed doses. The impact of MDOT interventions on modeled biological and clinical outcomes was compared for populations with mean rates of adherence (i.e., the mean percentage of prescribed doses taken by each member of the population who had not discontinued therapy) of 40%, 50%, 60%, and 70%. MDOT reduced the risk of virological failure, development of opportunistic infections, and death, yet increased the risk of drug resistance, for each adherence distribution among persons with detectable plasma virus loads. Over 1500 trials, for a population with 50% adherence to therapy and a 12-month period, MDOT increased the median rate of virological suppression from 13.2% to 37.0% of patients, decreased the rate of opportunistic infection from 5.7% to 4.3% of patients, and decreased the death rate from 2.9% to 2.2% of patients. In the same population, however, MDOT increased the rate of new drug resistance mutations from 1.00 to 1.41 per person during the 12-month period. The impact of MDOT was smaller in populations with higher levels of adherence. MDOT interventions will likely improve clinical outcomes in populations with low levels of adherence but may not be effective at preventing drug resistance in treatment-experienced populations. MDOT may be more effective in preventing drug resistance with potent regimens in treatment-naive patients.

Central venous catheter infections in AIDS patients receiving treatment for cytomegalovirus disease.

Central venous catheters (CVC) are commonly used to deliver daily intravenous medications to patients with AIDS, and CVC-associated bacterial infections have been a cause of substantial morbidity in such patients. Although previous studies have reported rates of CVC-associated infections in AIDS patients, none has compared rates by type of intravenous drug regimen used or by whether CVCs were percutaneously placed or tunneled under the skin. The charts of all AIDS patients diagnosed with cytomegalovirus (CMV) end-organ disease at San Francisco General Hospital between 1985 and 1990 were reviewed for evidence of CVC use and CVC-associated infection. Infection rates and time to infection were analyzed for serious CVC-associated infections (requiring catheter removal or hospitalization for intravenous antibiotic therapy) by type of anti-CMV therapy administered (ganciclovir versus foscarnet) and by type of CVC (tunneled versus percutaneous placement). Fifty-four patients had 72 CVCs in use for 11,622 days of intravenous anti-CMV therapy. There were 36 CVC-associated infections of which 23 were categorized as serious (rate, 0.20/100 catheter days). In patients receiving either ganciclovir or foscarnet therapy, we found no significant difference in serious infection rates or in infection-free survival time (216 vs. 282 days, p = 0.7). However, serious CVC infection-free time was significantly longer in patients with tunneled than with percutaneous CVCs (419 vs. 195 days, p = 0.018). The use of ganciclovir compared to foscarnet in the treatment of AIDS-related CMV disease was not associated with a greater risk of serious catheter-related infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study.

We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV naïve, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

Electric kettles as a source of human lead exposure.

Five hundred and seventy-four households in Ottawa were surveyed to evaluate water boiled in electric kettles as a source of lead exposure. Samples of boiled water exceeded the World Health Organization mandatory limit for drinking water (50 microgram/l) in 42.5% of the households. Excessive lead concentrations were observed in 62.8% of water samples from kettles more than 5 years old. Multiple regression analysis indicated that age, sex, and cigarette smoking habits, but not lead concentration in boiled water, nor weekly consumption of boiled water were significantly associated with blood-lead concentration. Lead exposure from electric kettles may be a significant problem only in infants receiving formula prepared with boiled water.

Expanding access to early HIV care: new challenges for federal health policy.

Advances in biomedical research have resulted in new standards for HIV treatment that involve earlier intervention with more complex combination antiretroviral therapy. This article examines the implications of these treatments for federally funded programs that provide HIV care and discusses mechanisms for making Medicaid and the AIDS Drug Assistance Program (ADAP) consistent with the treatment standards. The article provides a rationale for expanding access by expanding entitlement programs (Medicaid) rather than discretionary programs (ADAP). A potential legislative approach to Medicaid expansion is described. Cost projections suggest that this approach is feasible and would constitute a significant step toward increasing access to HIV care.

Household ventilation and tuberculosis transmission in Kampala, Uganda.

OBJECTIVE: To test the feasibility of measuring household ventilation and evaluate whether ventilation is associated with tuberculosis (TB) in household contacts in Kampala, Uganda. DESIGN: Adults with pulmonary TB and their household contacts received home visits to ascertain social and structural household characteristics. Ventilation was measured in air changes per hour (ACH) in each room by raising carbon dioxide (CO2) levels using dry ice, removing the dry ice, and measuring changes in the natural log of CO2 (lnCO2) over time. Ventilation was compared in homes with and without co-prevalent TB. RESULTS: Members of 61 of 66 (92%) households approached were enrolled. Households averaged 5.4 residents/home, with a median of one room/home. Twelve homes (20%) reported co-prevalent TB in household contacts. Median ventilation for all rooms was 14 ACH (interquartile range [IQR] 10-18). Median ventilation was 12 vs. 15 ACH in index cases' sleeping rooms in households with vs. those without co-prevalent TB (P = 0.12). Among smear-positive indexes not infected by the human immunodeficiency virus (HIV), median ventilation was 11 vs. 17 ACH in index cases' sleeping rooms in homes with vs. those without co-prevalent TB (P = 0.1). CONCLUSION: Our findings provide evidence that a simple CO2 decay method used to measure ventilation in clinical settings can be adapted to homes, adding a novel tool and a neglected variable, ventilation, to the study of household TB transmission.

Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata.

BACKGROUND: The human immunodeficiency virus (HIV) alters the presentation of pulmonary tuberculosis (PTB), but it remains unclear whether alterations occur at a CD4 cell threshold or throughout HIV infection. OBJECTIVE: To better understand the relationship between CD4 count and clinical and radiographic presentation of PTB. SETTING AND DESIGN: Initial presentations of culture-confirmed PTB patients evaluated at a Ugandan national TB referral center and an affiliated research unit were compared by HIV status and across 11 CD4 cell count strata: 0-50 to >500 cells/µl. RESULTS: A total of 873 HIV-infected PTB cases were identified. Among HIV-infected PTB cases with CD4 < 50, 21% had a normal chest X-ray (CXR) vs. 2% with CD4 > 500, with a continuous trend across CD4 strata (test for trend, P < 0.001). All radiographic manifestations of PTB displayed significant trends across CD4 strata. HIV-infected vs. non-HIV-infected patients had no significant difference in CXR findings of miliary patterns or pleural effusion at CD4 > 100, normal CXR or fibrosis at CD4 > 150, adenopathy at CD4 > 250, and cavitation or upper lung disease at CD4 > 300. Twenty-three per cent of co-infected cases with CD4 < 50 and 1% with CD4 > 500 had negative acid-fast bacilli (AFB) smears, with a significant trend between (P < 0.001). CONCLUSION: Variations in CXR appearance and AFB smear correlate with CD4 decline in significant, continuous trends.

It's not just what you say: relationships of HIV dislosure and risk reduction among MSM in the post-HAART era.

In the post-HAART era, critical questions arise as to what factors affect disclosure decisions and how these decisions are associated with factors such as high-risk behaviors and partner variables. We interviewed 1,828 HIV-positive men who have sex with men (MSM), of whom 46% disclosed to all partners. Among men with casual partners, 41.8% disclosed to all of these partners and 21.5% to none. Disclosure was associated with relationship type, perceived partner HIV status and sexual behaviors. Overall, 36.5% of respondents had unprotected anal sex (UAS) with partners of negative/unknown HIV status. Of those with only casual partners, 80.4% had >1 act of UAS and 58% of these did not disclose to all partners. This 58% were more likely to self-identify as gay (versus bisexual), be aware of their status for <5 years and have more partners. Being on HAART, viral load and number of symptoms were not associated with disclosure. This study - the largest conducted to date of disclosure among MSM and one of the few conducted post-HAART - indicates that almost 1/5th reported UAS with casual partners without disclosure, highlighting a public health challenge. Disclosure needs to be addressed in the context of relationship type, partner status and broader risk-reduction strategies.

Risk factors for early hospital readmission in patients with AIDS and pneumonia.

OBJECTIVE: To determine risk factors for early readmission to the hospital in patients with AIDS and pneumonia. DESIGN: Case-control analysis. SETTING: A municipal teaching hospital serving an indigent population. PATIENTS: Case patients were all AIDS patients hospitalized with Pneumocystis carinii pneumonia or bacterial pneumonia between January 1992 and March 1995 who were readmitted for any nonelective reason within 2 weeks of discharge (n = 90). Control patients were randomly selected AIDS patients admitted during the study period who were not early readmissions (n = 87), matched by proportion of Pneumocystis carinii to bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: Demographics, social support, health-related behaviors, clinical aspects of the acute hospitalization, and general medical status were the main predictors measured. RESULTS: Patients were at significantly increased risk of early readmission if they left the hospital unaccompanied by family or friend (odds ratio [OR] 4.76; 95% confidence interval [CI] 2.06, 11.0; p =.0003), used crack cocaine (OR 3.40; 95% CI 1.02, 11.3; p =. 046), had one or more coincident AIDS diagnoses (OR 3.65; 95% CI 1. 44, 9.26; p =.0065), or had been admitted in the preceding 6 months (OR 2.82; 95% CI 1.21, 6.57; p =.016). Demographic characteristics, alcoholism, intravenous drug use, illness severity on admission, and length of hospitalization did not predict early readmission. CONCLUSIONS: Absence of companion at discharge and crack use were important risk factors for early readmission in patients with AIDS and pneumonia. Additional AIDS comorbidity and recent antecedent hospitalization were also risk factors; however, demographics and measures of acute illness during index hospitalization did not predict early readmission.

Antibodies to epitopes of herpes simplex virus type 1 glycoprotein B (gB) in human sera: analysis of functional gB epitopes defined by inhibition of murine monoclonal antibodies.

The epitopes on herpes simplex virus (HSV) glycoprotein B (gB) recognized by sera of 23 patients with well-characterized HSV infection were studied. Twelve epitope-specific monoclonal antibodies with neutralization (NT) or antibody-dependent cellular cytotoxicity (ADCC) activities were used in competitive ELISA binding inhibition studies. The sera were additionally analyzed for homologous viral type NT, ADCC activity, and gB-reactive antibody by ELISA. Seroconversion was observed in each assay during convalescence. Relative type specificity for sera from HSV-1-infected but not from HSV-2-infected individuals was demonstrated in the ADCC assay. Sera from HSV-infected patients contained antibodies recognizing 9 of 12 epitopes, representing 5 of the 6 characterized antigenic domains of gB tested. Two of the epitopes were blocked in a type-specific fashion. The incidence of epitopic recognition increased gradually with time and was delayed compared with the detection of functional ADCC or NT activity and overall antibody recognition of gB in the ELISA.

Changes in AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993.

BACKGROUND: During the first decade since the recognition of the acquired immunodeficiency syndrome (AIDS), new therapies have been introduced and the frequency of clinical manifestations has changed. The impact of these changes on AIDS survival, however, has not been well characterized. DESIGN: A prospective cohort study of the outcomes of human immunodeficiency virus (HIV) infection. SETTING: Homosexual and bisexual men residing in San Francisco, Calif, recruited in 1983 and 1984 for two prospective studies and followed up for more than 9 years with clinical examinations. PARTICIPANTS: A total of 761 HIV-positive homosexual and bisexual men. MAIN OUTCOME MEASURES: Survival time from a CD4 lymphocyte count at 0.20 x 10(9)/L (200/microL) and from a clinical AIDS diagnosis to death. RESULTS: Median survival time from a CD4 lymphocyte count at 0.20 x 10(9)/L increased from 28.4 months in the October 1983 to November 1986 period to 40.1 months in the November 1986 to November 1988 period and is estimated at 38.1 months in the November 1988 to February 1993 period. Patients diagnosed with Pneumocystis carinii pneumonia (PCP) accounted for most of this increase with a gain in median survival time of 9.7 months (P = .0009), compared with a nonsignificant decline in the survival time of those patients without a PCP diagnosis. Multivariate analysis showed that rate of CD4 lymphocyte loss (P < .001) and receipt of both PCP prophylaxis and antiretroviral therapy (P = .04) were significantly associated with longer survival time, whereas antiretroviral therapy alone was not (P = .81). Time to death from a clinical AIDS diagnosis was 14.7 months in the 1983 to 1986 period, 19.1 months in the 1986 to 1988 period, and an estimated 15.7 months in the 1988 to 1993 period. CONCLUSIONS: Survival time from a CD4 lymphocyte count at 0.20 x 10(9)/L has improved significantly by about 1 year; yet survival time using the 1987 AIDS case definition has shown small improvement. The largest increase in survival time from a CD4 lymphocyte count at 0.20 x 10(9)/L was in patients diagnosed with PCP, suggesting that PCP prophylaxis and treatment were more important factors in longer survival time than antiretroviral therapy.

Physician-assisted suicide and patients with human immunodeficiency virus disease.

BACKGROUND: Data are limited on the attitudes and practices of physicians regarding assisting the suicide of patients with human immunodeficiency virus (HIV) disease. METHODS: Between November 1994 and January 1995, we used an anonymous, self-administered questionnaire to survey all 228 physicians in the Community Consortium, an association of providers of health care to patients infected with HIV in the San Francisco Bay area. The responses were compared with those in a 1990 survey of consortium physicians. Physician-assisted suicide was defined as "a physician providing a sufficient dose of narcotics to enable a patient to kill himself." Respondents were to "assume that the patient is a mentally competent, severely ill individual facing imminent death." RESULTS: One hundred eighteen of the questionnaires were evaluated. Respondents reported a mean of 7.9 "direct" and 13.7 "indirect" requests from patients for assistance. In responses based on a case vignette, 48 percent of the physicians said they would be likely or very likely to grant the request of a patient with the acquired immunodeficiency syndrome (AIDS) for assistance in a suicide, as compared with 28 percent of the respondents in 1990. Asked to estimate the number of times they had granted the request of a patient with AIDS for assistance in committing suicide, 53 percent said they had done so at least once (mean number of times, 4.2; median, 1.0; range, 0 to 100). In a multivariate analysis, factors positively associated with having, in fact, assisted a suicide were having had a higher number of patients with AIDS who had died, a higher number of indirect requests from patients for assistance, a stated gay, lesbian, or bisexual orientation on the part of the physician, and a higher "intention to assist" score (as calculated from the physician's responses to the case vignette). CONCLUSIONS: Within a group of physicians caring for patients with HIV disease, the acceptance of assisted suicide increased between 1990 and 1995. A majority of respondents in 1995 said they had granted a request for assisted suicide from a patient with AIDS at least once.

Interleukin-12 administered in vivo decreases human NK cell cytotoxicity and antibody-dependent cellular cytotoxicity to human immunodeficiency virus-infected cells.

Persons infected with human immunodeficiency virus (HIV) have cellular cytotoxicity defects. Interleukin (IL)-12 is a potent stimulator of cytotoxicity. Fifteen HIV-infected patients were studied in a phase 1, single-dose escalation trial of human recombinant IL-12. One day after subjects received an IL-12 dose of 300 or 1000 ng/kg, they had a reduction in absolute lymphocyte count and peripheral blood mononuclear cell recovery. In evaluable patients 24 h after IL-12 administration, there was a 31% reduction overall in NK cell cytotoxicity (NKC) to HIV-infected cells at all doses and a 52% reduction in antibody-dependent cellular cytotoxicity (ADCC) at doses of 300 and 1000 ng/kg. In vitro incubation of patients' cells with IL-12 (before IL-12 administration) for 24 h increased NKC but had no effect on ADCC. The paradoxic acute reduction in cell number and cytotoxicity in vivo may be due to NK cell trafficking or regulatory cytokine mechanisms not apparent in vitro.

Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial.

BACKGROUND: Increasing Plasmodium falciparum resistance to chloroquine in sub-Saharan Africa necessitates use of alternative antimalarial agents. Affordable alternative treatments include sulfadoxine/pyrimethamine and amodiaquine. Combination of antimalarial agents can increase therapeutic efficacy and delay emergence of drug resistance. We compared the efficacy of sulfadoxine/pyrimethamine, amodiaquine, and an amodiaquine/sulfadoxine/pyrimethamine combination for treatment of uncomplicated malaria in a region of high chloroquine resistance. METHODS: Patients with symptoms of uncomplicated falciparum malaria and confirmed disease in Kampala, Uganda, were randomly assigned to receive sulfadoxine/pyrimethamine (25 mg/kg sulfadoxine, and 1.25 mg/kg pyrimethamine) plus placebo; amodiaquine (25 mg/kg) plus placebo; or amodiaquine plus sulfadoxine/pyrimethamine. Patients were followed up for 14 days, and clinical and parasitological outcomes were assessed. FINDINGS: 90% (400/445) of patients enrolled in the study successfully completed 14 days of follow-up. Treatment failure based on clinical criteria occurred in 13 of 131 (10%) patients on sulfadoxine/ pyrimethamine, nine of 131 (7%) on amodiaquine, and four of 138 (3%) on amodiaquine/sulfadoxine/pyrimethamine. Based on parasitological criteria, treatment failed in 26%, 16%, and 10% of these patients, respectively. Amodiaquine/sulfadoxine/pyrimethamine was significantly more effective than sulfadoxine/pyrimethamine alone in children aged younger than 5 years (clinical failure in 3.5% vs 13.9%, respectively, risk difference 10.4% [95% CI, 1.6-19.3] p=0.021; parasitological failure in 12.8% vs 26.4%, risk difference 13.6% [1.2-26.0] p=0.041). INTERPRETATION: Sulfadoxine/pyrimethamine, amodiaquine, and amodiaquine/sulfadoxine/pyrimethamine were all effective for treatment of uncomplicated falciparum malaria in Uganda. The amodiaquine/sulfadoxine/pyrimethamine combination was the most effective, and could be the optimum low-cost alternative to chloroquine in Africa.