HIV immunosuppression and antimalarial efficacy: sulfadoxine-pyrimethamine for the treatment of uncomplicated malaria in HIV-infected adults in Siaya, Kenya

BACKGROUND: The altered immune response of persons with human immunodeficiency virus (HIV) infection could result in increased rates of antimalarial treatment failure. We investigated the influence of HIV infection on the response to sulfadoxine-pyrimethamine treatment. METHODS: Febrile adults with Plasmodium falciparum parasitemia were treated with sulfadoxine-pyrimethamine and were monitored for 28 days. HIV status and CD4 cell count were determined at study enrollment. RESULTS: Of the adults enrolled in the study, 508 attended all follow-up visits, including 130 HIV-uninfected adults, 256 HIV-infected adults with a high CD4 cell count (> or =200 cells/ micro L), and 122 HIV-infected adults with a low CD4 cell count (<200 cells/ micro L). The hazard of treatment failure at day 28 of follow-up was significantly higher for HIV-infected adults with a low CD4 cell count (20.5%) than for HIV-uninfected adults (7.7%). Anemia (hemoglobin level, <110 g/L) modified the effect of HIV status on treatment failure. When we controlled for fever and parasite density, the hazard of treatment failure for HIV-infected adults with a low CD4 cell count and anemia was 3.4 times higher than that for HIV-uninfected adults (adjusted hazard ratio, 3.38; 95% confidence interval, 1.56-7.34). CONCLUSIONS: HIV-infected persons with a low CD4 cell count and anemia have an increased risk of antimalarial treatment failure. The response to malaria treatment in HIV-infected persons must be carefully monitored. Proven measures for the control and prevention of malaria must be incorporated into the basic package of services provided by HIV/acquired immunodeficiency syndrome care and treatment programs in malarious areas.     

Hyponatraemia and hypokalaemia in adults with uncomplicated malaria in Thailand

In a retrospective study of 1415 patients aged 15 and over, we determined the incidence of clinically important hyponatraemia and hypokalaemia in adults with uncomplicated malaria. On admission, serum concentrations of sodium (135-145 mmol/L) and potassium (3.5-5.0 mmol/L) were found outside these reference ranges in 81% of patients. Severe hypokalaemia (K+ <3.0 mmol/L) and severe hyponatraemia (Na+ <125 mmol/L occurred in 4.4% and 0.6% of the patients, respectively. For hypokalaemia (43%) and hyponatraemia (37%), hypovolaemia, blood urea to creatinine ratio and high serum glucose (>100 mg/dL) were all independent factors (P < 0.001). Other independent predictors for hypokalaemia were Plasmodium vivax infection, female gender; and for hyponatraemia, P. falciparum infection, male gender, concentrations of G-6-PD and serum bicarbonate.     

Contrasting functions of IgG and IgE antimalarial antibodies in uncomplicated and severe Plasmodium falciparum malaria

Plasmodial infection results in a significant elevation of the blood concentrations of immunoglobulins including IgE. Two well-characterized groups of adult Thai patients with either uncomplicated or severe Plasmodium falciparum malaria were studied over a period of four weeks. The mean parasitemias were approximately three-fold higher in patients with severe malaria than in those with uncomplicated disease. The mean concentrations of both total IgG and IgG antiplasmodial antibodies tended to be highest in the group with uncomplicated disease while total IgE and IgE antibodies were higher in the group with severe disease. The IgE antibodies detected in approximately 65% of the patients were positively correlated to parasitemia. These results suggest that antiplasmodial IgG antibodies are involved in reducing the severity of P. falciparum malaria, while IgE antibodies may contribute to the pathogenesis of this infection.     

Therapeutic efficacies of antimalarial drugs in the treatment of uncomplicated, Plasmodium falciparum malaria in Assam, north-eastern India

In the Indian state of Assam, the current therapeutic efficacies of the drugs commonly used in the area for the treatment of uncomplicated, Plasmodium falciparum malaria were investigated. As is routine in this area, subjects found positive for P. falciparum malaria were initially treated with chloroquine (CQ). They were given sulfadoxine-pyrimethamine (SP) if this treatment failed, and subsequently quinine if the SP failed. The protocol of the World Health Organization's extended in-vivo test was used to follow parasite clearance and clinical cure. Therapeutic response was assessed by comparing the baseline (day-0) level of parasitaemia with that observed on day 3. Many (75.7%) of the 144 evaluable subjects were treatment successes after CQ, but six early (4.2%) and 29 (20.1%) late CQ-treatment failures were observed. Of the 34 CQ-treatment failures followed, 31 (91.2%) responded adequately to SP but the other three were early (one) or late (two) SP-treatment failures. Two (66.7%) of the SP-treatment failures responded adequately to parenteral quinine but the other (a late quinine-treatment failure) had to be given an artemisinin derivative to achieve a clinical cure. The foci in which multidrug-resistant cases of malaria are developing in India need to be identified quickly, so that such cases can be cured before the mutant strains of P. falciparum that are resistant to several drugs have a chance to become more widespread.     

Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana

The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control in sub-Saharan Africa. We undertook a study on the efficacy of some antimalarial drugs in 2003 with the view of supporting the National Malaria Control Programme in the review of the antimalarial drug treatment policy in Ghana. Children aged 6-59 months with signs/symptoms of uncomplicated malaria including axillary temperature > or =37.5 degrees C; mono infection with P. falciparum; and parent's willingness to give consent, were randomized into four treatment groups and followed up for a maximum of 28 days. The treatment groups were chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine+artesunate (ADQ+ART) combination, and artemether+lumefantrine (Coartem) combination. Clinical evaluation of 168 children studied showed that cumulative pcr-corrected cure rates on day 28 were 100% for ADQ+ART; 97.5% for coartem, 60% for SP and 25% for CHQ. The artemisinin-based combinations effected rapid fever and parasite clearance. Prevalence of gametocytaemia was highest in the SP group whilst the CHQ group did not show any significant changes in haemoglobin levels during the follow-up period. The findings are in agreement with current recommendations for using artemisinin-based combinations for treating uncomplicated malaria in areas of high CHQ failure such as Ghana.     

Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults

BACKGROUND: Infection with intestinal helminths may stimulate dysfunctional immune responses in human immunodeficiency virus (HIV)-infected persons. Studies have yielded conflicting results regarding the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA.Methods. We conducted a prospective study of 54 HIV-1- and helminth-coinfected and 57 HIV-1-infected, helminth-uninfected asymptomatic adults living in Lusaka, Zambia, to assess the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA. RESULTS: Median baseline viral load was 0.33 log(10) copies/mL lower in the helminth-infected group than in the uninfected group. Mean viral load between pretreatment and posttreatment visits increased in the helminth-infected (mean, 4.23 vs. 4.29 log(10) copies/mL; P=.6) and helminth-uninfected (mean, 4.39 vs. 4.52 log(10) copies/mL; P=.2) groups. Helminth-infected participants with high pretreatment viral loads had a mean 0.25-log(10) copies/mL decrease after treatment (P=.3), and helminth-uninfected participants had a mean 0.02-log(10) copies/mL decrease (P=.8). CONCLUSIONS: We did not find an overall association between treatment of intestinal helminth infections and reduction in viral load in coinfected adults. Future studies may need to focus on adults with intense helminth infections who live in rural areas or on adults or children who harbor higher helminth burdens and plasma concentrations of HIV-1 RNA.     

Folic acid treatment of Zambian children with moderate to severe malaria anemia

Whether administration of folic acid to children with malaria anemia is helpful is controversial. Therefore, we conducted a randomised, placebo-controlled trial of 14 days of treatment with folic acid (1 mg/d) in Zambian children with malaria anemia treated with either sulfadoxine/pyrimethamine (SP) or atovaquone/proguanil (AP). Among children who received SP, the prevalence of parasitemia was higher in children treated with folic acid than among those given placebo at days 3, 7, and 14 after the start of treatment, and the difference at day 3 was statistically significant (P = 0.013). Folic acid treatment had no effect on parasitemia in children treated with AP. Administration of folic acid led to a small increase in packed cell volume over that seen in the placebo group at days 14 and 28 after the start of treatment.     

Efficacy of methylene blue monotherapy in semi‐immune adults with uncomplicated falciparum malaria: a controlled trial in Burkina Faso

Objective To assess the efficacy of methylene blue (MB) monotherapy in semi‐immune adults with uncomplicated malaria in Burkina Faso. Methods In an open‐label controlled phase II study with 60 semi‐immune adults with uncomplicated falciparum malaria in Nouna, north‐western Burkina Faso, MB monotherapy (390 mg twice daily) was given sequentially to groups of 20 adults for 7 days (MB7), 5 days (MB5) and 3 days (MB3), respectively. The primary outcome was the rate of adequate clinical and parasitological response (ACPR) on day 28 of follow‐up. Results Of the study population, 27/58 (47%) and 5/51 (10%) patients still had parasites on days 2 and 3, respectively, of follow‐up resulting in 9/58 (16%) early treatment failures. By day 14, no recrudescence was observed but in 4/19 (MB5) and 2/20 (MB3) individuals by day 28. The PCR‐corrected rate of ACPR was 72%, 58% and 85% in groups 7, 5 and 3, respectively, by per protocol analysis. Self‐limiting dysuria was the most frequent adverse event. Conclusions MB acts slowly against the blood stages of P. falciparum. MB alone needs to be given for at least 7 days to be efficacious in the treatment of falciparum malaria but should be used in combination with a fast acting antimalarial.     

Differential regulation of IgG subclasses and IgE antimalarial antibody responses in complicated and uncomplicated Plasmodium falciparum malaria

The aim of this study was to assess the immunoglobulin (Ig)-subclass distribution of antimalarial antibody responses in 110 and 169 Thai patients with complicated and uncomplicated Plasmodium falciparum malaria, respectively. Antimalarial plasma IgG subclasses and IgE antibody levels against a crude malaria blood stages, and antigen preparation were determined using enzyme-linked immunosorbent assay (ELISA). On admission, the levels of anti-P. falciparum IgG1, IgG2 and IgG3 were significantly lower in patients with complicated malaria than uncomplicated malaria (IgG1, P < 0.0001; IgG2, P < 0.0001; IgG3, P < 0.0001). The levels of antimalarial IgE were slightly lower, but not statistically significant (P = 0.389) in the complicated malaria. After adjusting all antibody levels and age, anti-P. falciparum IgG3 levels remained significantly associated with complicated malaria. None of the other antibody concentrations showed statistically significant associations with complicated malaria. The anti-P. falciparum IgG3 levels were related to the IgG1 as well as IgG2 levels. A correlation between anti-P. falciparum IgG2 and IgE was observed in the complicated malaria group, and this may indicate their roles in the severity of disease. Our data suggest that anti-P. falciparum IgG3 is associated with a reduced risk of complicated malaria and that antimalarial Ig-subclasses are differently regulated in patients with complicated and uncomplicated malaria.     

Antibodies against malaria sporozoites in patients with acute uncomplicated malaria and patients with cerebral malaria

Serum samples from 95 patients with acute uncomplicated falciparum malaria (AM) and 95 patients with cerebral malaria (CM) were tested by the indirect immunofluorescent assay (IFA) for IgG and IgM antibodies against Plasmodium falciparum and P. vivax sporozoites. Forty-six (48%) CM patients were positive for antibodies against P. falciparum sporozoites whereas only 23 (24%) were positive for antibodies against P. vivax sporozoites (P less than 0.002). A similar result was obtained in AM patients. However, CM patients had significantly lower mean IgG anti-sporozoite titer for P. falciparum than did AM patients (P less than 0.05), especially when only anti-sporozoite antibody-positive CM and AM patients were compared (P less than 0.0005), suggesting that CM patients had relatively less exposure and were probably less immune to malaria than were AM patients. The persistence of anti-sporozoite antibodies also was investigated in paired sera taken 63 days apart from 108 patients with acute falciparum malaria. There were significant decreases in the mean antibody titers in the follow-up sera during the period of stay in the malaria-free area. It was proposed that determination of anti-sporozoite antibody be made as a substitute for, or in addition to, anti-blood stage antibody for seroepidemiological study of malaria, especially in the monitoring of the success of the malaria control program.     

Anti-NANP antibody and treatment efficacy in patients with acute uncomplicated falciparum malaria attacks

African patients originating from the hypoendemic, urban area of Greater Dakar (Senegal, West Africa) who presented with an acute Plasmodium falciparum infection were studied using an in-vivo chloroquine sensitivity assay for 28 days. Forty-seven patients with acute malaria infections were treated with 25 mg/body weight of chloroquine. Adequate responses to treatment were observed in 24 patients (51%), whereas 23 (49%) were resistant. On the day of admission, these two groups of patients were comparable with respect to age, level of parasitemia and delay before initiation of treatment, but not with respect to gametocyte prevalence which was higher in patients resistant to therapy (48%) than in those who responded to treatment (17%). In order to evaluate whether the therapeutic response was associated with any given specific immune response, antibody activities against different stages of the parasite cycle were evaluated: anti-NANP repeats (i.e. antisporozoite stage antigen), anti-Pfs 45 kDa (i.e. antigametocyte stage antigen), and anti-MSP3 (i.e. antimerozoite stage antigen) antibodies were measured by ELISA at day 0 (i.e. on the day of admission and before initiation of treatment), day 7 and day 28. No significant differences between treatment-sensitive and treatment-resistant infections were observed for antibody prevalences and optical densities, except at day 0, when the prevalence of antibodies against NANP repeats was 2.4 times more frequent in the group of patients with a propitious response to treatment: 62.5% of the patients with an infection sensitive to chloroquine had anti-NANP antibodies, whereas only 26.1% of the patients resistant to chloroquine treatment had such a humoral response. These observations are discussed in relation to (1) the finding that gametocyte prevalence was markedly increased at a time when resistance to antimalarial treatment was observed; (2) the possibility that the efficacy of the therapeutic response could be the result of the combined effects of treatment and the individual immune status of the patients at the time of drug cure; and (3) the presence of detectable anti-NANP activity as potential indicator of the level of premunition acquired in an area of low and seasonal malaria transmission.     

Severe anaemia in Zambian children with Plasmodium falciparum malaria

BACKGROUND: Severe anaemia and cerebral malaria are highly prevalent complications of Plasmodium falciparum malaria among African children. The mechanisms of severe malarial anaemia, and the relative importance of this condition in comparison to cerebral malaria, are not known for many regions of Africa. METHODS We reviewed the records of 6200 children up to 6 years of age admitted to one rural Zambian hospital between 1994 and 1996. Severe malarial anaemia was defined as an haemoglobin concentration < 5.0 g/dl in a patient with asexual forms of P. falciparum in the peripheral blood. Cerebral malaria was defined as impaired consciousness (Blantyre coma score < 5) not attributable to any other cause in a patient with a positive malaria smear. RESULTS Severe malarial anaemia was found in 590 children (9.5% of paediatric admissions) and strictly defined cerebral malaria occurred in 286 children (4.6% of paediatric admissions); 98 of these patients had the combination of both complications. Severe malarial anaemia correlated strongly with the degree of parasitaemia, with malnutrition as indicated by low weight for age, with absence of fever and with presentation late in the malaria season. In comparison, patients with cerebral malaria were more often febrile and presented earlier in the malaria season. The case fatality rate of severe malarial anaemia (0.088) was about half that of cerebral malaria (0.189), but because severe malarial anaemia was more common, these two forms of complicated malaria were implicated in similar numbers of in-hospital paediatric deaths. CONCLUSION Severe anaemia is a more common complication of P. falciparum malaria in hospitalized Zambian children than cerebral malaria and is associated with a similar number of deaths. Malnutrition and changes in immune response patterns due to prolonged exposure to P. falciparum may contribute to the development of this complication.     

Cell-mediated immune responses to autologous virus in HIV-1-seropositive individuals after treatment with an HIV-1 immunogen

OBJECTIVE: We hypothesized that cell mediated immune responses to an HIV-1 immunogen (whole-killed, gp120-depleted HIV-1 in IFA, REMUNE) would include those to autologous virus. METHODS: Five chronically HIV-1 infected individuals were examined for HIV-specific immune responses to their own virus (autologous viral antigen) after treatment with an HIV-1 immunogen. RESULTS: Subjects had low proliferative responses to HIV and p24 antigens prior to immunization and mounted strong lymphocyte proliferative responses to the immunizing HIV-1 virus, native p24, and autologous viral antigen post immunization. Similarly, subjects produced low amounts of interferon-gamma in response to HIV and p24 antigens prior to immunization and increased their interferon-gamma production in response to HIV-1, native p24, and to autologous antigen post-immunization. Furthermore, beta-chemokine responses measured as migratory inhibitory protein-1beta production were low at baseline in response to HIV-1 and native p24 antigens and were enhanced post immunization to HIV-1, native p24, and autologous antigen. CONCLUSIONS: In this study HIV-specific immune responses to autologous virus were observed after treatment with an HIV-specific immunogen.     

Chloroquine for the treatment of uncomplicated malaria in Guyana

At a public hospital in Georgetown, Guyana, 44 patients seeking treatment for symptomatic, slide-confirmed malaria were given standard chloroquine (CQ) therapy and followed for 28 days. The patients apparently had pure infections with Plasmodium falciparum (14), P. vivax (13) or P. malariae (one), or mixed infections either of P. falciparum and P. vivax (17) or of P. falciparum, P. malariae and P. vivax (two). Each received supervised treatment with 10 mg CQ base/kg on each of days 0 and 1, and 5 mg/kg on day 2. On the day of enrollment (day 0), the patients complained of fever (100%), headache (100%), malaise (94%), myalgia (79%), nausea (67%), vertigo (49%) and vomiting (33%). Many (39%) were ill enough to confine themselves to bed. On day 4, fewer of the subjects complained of fever (15%), headache (15%), malaise (6%), myalgia (21%), nausea (6%), vertigo (24%) or vomiting (0%) despite the relatively high (>48%) risk of therapeutic failure. The cumulative incidence of parasitological failure against P. falciparum was 15% at day 4, 33% at day 7 and 48% at day 14. All of the P. vivax and P. malariae infections cleared before day 4 and none recurred by day 7. Two infections with P. vivax recurred later (on day 14 or 28) but in the presence of less than adequate, whole-blood concentrations of CQ plus desethyl-chloroquine (i.e. <100 ng/ml). Taken together, the results indicate a high risk of therapeutic failure of CQ against P. falciparum but also indicate that resistance to CQ in P. vivax occurs infrequently in Guyana.     

Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.     

Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults

BACKGROUND: Falciparum malaria and HIV-1 infection are two of the most important health problems facing sub-Saharan Africa. No convincing evidence of an association between symptomatic malaria and HIV-1 infection has been found. OBJECTIVE: To investigate the effect of HIV-associated immunosuppression on malarial fever rates. DESIGN: An observational cohort study in HIV-specific, primary healthcare clinics in Entebbe, Uganda, on 1371 HIV-1-infected adults participating in a randomized trial of 23-valent pneumococcal vaccine. METHODS: Cohort members underwent routine 6 monthly surveillance and had open clinic access when sick. Episodes of fever were assessed according to standardized protocols. Rates of malaria are described according to HIV immune status determined by CD4 T cell counts. RESULTS: Incidence rates of Plasmodium falciparum malarial fever showed a marked inverse relationship with CD4 T cell count; 140, 93 and 57 cases per 1000 pyo for CD4 T cell groups < 200, 200--499 and > 500 respectively, P < 0.001. Malarial fever definitions incorporating parasite density criteria (derived from asymptomatic surveillance) to correct for chance findings of fever and P. falciparum parasitaemia, did not affect the association of incidence rates with immunosuppression. CONCLUSION: These data support an interaction between symptomatic P. falciparum and HIV. Emphasis on mosquito avoidance measures should be an important component of education and counselling of HIV/AIDS patients in malaria-endemic areas, and suggests an additional HIV-related public health problem in Africa.     

Polymorphisms of molecular markers of antimalarial drug resistance and relationship with artesunate-mefloquine combination therapy in patients with uncomplicated Plasmodium falciparum malaria in Thailand

The aim of this study was to investigate the association between genetic polymorphisms of Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1), and P. falciparum ATPase (pfatp6) and clinical outcome after a three-day mefloquine-artesunate combination therapy in 134 patients with uncomplicated Plasmodium falciparum malaria in an area with multidrug resistance along the Thailand-Myanmar border. Analysis of gene mutation and amplification were performed by nested real-time polymerase chain reaction and SYBR Green I real-time polymerase chain reaction, respectively. The mutation for pfcrt (codons 76, 220, 271, 326, 356, and 371) was found in all isolates (100%), whereas no mutation of pfmdr1 (codon 86) and pfatp6 (codons 37, 693, 769, 898) was found. The Pfmdr1 copy number was significantly higher in isolates with recrudescence (median number = 2.44) compared with a sensitive response (median number = 1.44). The gene copy number was also found to be significantly higher in paired isolates collected before treatment and at the time of recrudescence. All isolates carried one pfatp6 gene copy.