Francis Ssali | Doetsk Christian University (original) (raw)

Papers by Francis Ssali

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Host immunity plays an important role in response to antimalarial therapy but is poorly understoo... more Host immunity plays an important role in response to antimalarial therapy but is poorly understood. To test whether T cell activation is a risk factor for antimalarial treatment failure, we studied CD4 + and CD8 + T cell activation in 31 human immunodeficiency virus-negative Ugandan patients 5-37 years of age who were treated for uncomplicated Plasmodium falciparum malaria. Increased CD4 + T cell activation, as indicated by co-expression of HLA-DR and CD38, was an independent risk factor for treatment failure (hazard ratio ‫ס‬ 2.45, 95% confidence interval ‫ס‬ 1.02-5.89, P ‫ס‬ 0.05) in multivariate analysis controlling for age, baseline temperature, and pre-treatment parasite density. The results provide insight into the role of cellular immunity in response to antimalarial therapy and underscore the need to investigate the mechanisms behind immune activation.

Antimicrobial Agents and Chemotherapy, 2010

/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a d... more /150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n ‫؍‬ 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n ‫؍‬ 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n ‫؍‬ 20), nevirapine (n ‫؍‬ 18), and no NNRTI (n ‫؍‬ 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) was 110.1 (34%) g ⅐ h/liter. For efavirenz, the geometric mean lopinavir AUC 0-12 (%CV) values were 91.8 g ⅐ h/liter (58%), 65.7 g ⅐ h/liter (39%), and 54.0 g ⅐ h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P ‫؍‬ 0.002) and 0.82 (90% CI, 0.68 to 0.99; P ‫؍‬ 0.09),

Journal of The International Aids Society, 2008

With NNRTI, the recommended dose of lopinavir/r (LPV/ r) is 4 capsules (533/133 mg) BD. With LPV/... more With NNRTI, the recommended dose of lopinavir/r (LPV/ r) is 4 capsules (533/133 mg) BD. With LPV/r tablets, the closest doses are 2 tablets (400/100 mg) BD or 3 tablets [tabs] (600/150 mg) BD. Improved bioavailability of the tablet suggests that 2 tabs BD should be sufficient, but PK data are few and generally from Caucasians.

Lancet, 2010

Background-Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa... more Background-Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults.

Journal of The International Association of Physicians in Aids Care (jiapac), 2007

Aids Research and Human Retroviruses, 2009

We set out to investigate whether there are clinically significant consequences when children wit... more We set out to investigate whether there are clinically significant consequences when children with perinatal exposure to single-dose nevirapine are initiated on a nonnucleoside reverse transcriptase inhibitor (NNRTI) containing a highly active antiretroviral therapy (HAART) regimen. We carried out a chart and database review of 104 HIV-infected children, who had initiated HAART with an NNRTI at JCRC and were less than or equal to 5 years of age, 35 (33.7%) of whom had prior exposure to perinatal single-dose nevirapine. We studied the viral load and CD4 percentage at baseline, at week 24, and at week 48 after the start of HAART in children exposed and not exposed to perinatal single-dose nevirapine, as well as the results of genotypic resistance testing done for the children who had failed to achieve virologic suppression on HAART. At weeks 24 and 48 after initiating HAART, children not exposed to single-dose nevirapine were 3.28 times [OR = 3.28, 95% CI: (1.37 to 9.20), p = 0.0167] and 3.47 times [OR = 3.47, 95% CI: (1.28 to 9.37), p = 0.0091] more likely to achieve virologic suppression compared to children exposed to single-dose nevirapine, respectively. However, the CD4 cell response at weeks 24 and 48 was not worse in the children exposed to single-dose nevirapine. In 10 children with perinatal exposure to single-dose nevirapine, NNRTI resistance mutations, mostly K103N, Y181C, and G109A, were identified. HIV-infected children with perinatal exposure to single-dose nevirapine are less likely to achieve short-term virologic suppression when started on an NNRTI-containing regimen, when compared to those who were not exposed to it, probably because the exposure predisposes them to developing NNRTI resistance mutations.

Aids, 2007

... J Infect Dis 2006; 193:1195–1201. 4. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG... more ... J Infect Dis 2006; 193:1195–1201. 4. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG. ... Victor Musiime, Francis Ssali, Hilda Kizito, Cissy Kityo and Peter Mugyenyi, Joint Clinical Research Centre, Kampala, Uganda. ...

Jaids-journal of Acquired Immune Deficiency Syndromes, 2007

Data on discontinuation and modification of highly active antiretroviral therapy (HAART) are scar... more Data on discontinuation and modification of highly active antiretroviral therapy (HAART) are scarce among sub-Saharan African populations. We sought to estimate the prevalence and to identify factors associated with these phenomena in our resource-limited setting. Patients were recruited into this cross-sectional study from 2 treatment centers in Kampala, Uganda. Discontinuation and modification were assessed by self-report using semistructured quantitative and unstructured qualitative interviews. Discontinuation was defined as the simultaneous stopping of all antiretrovirals for at least 1 month, and modification as the changing of at least 1 antiretroviral used in an initial HAART regimen. Factors independently associated with each outcome were assessed using multivariate logistic regression. Of 686 subjects evaluated, 94 (13.7%) had ever discontinued therapy, whereas 175 (25.5%) had ever modified their regimen. The median CD4 count was 175 (interquartile range: 66-297) cells/microL. Factors associated with discontinuation were HAART experience before starting the current regimen (odds ratio [OR] = 3.70, 95% confidence interval [CI]: 2.13 to 6.25), use of alternative medicines (OR = 2.18, 95% CI: 1.06 to 4.47), hospitalization (OR = 2.36, 95% CI: 1.32 to 4.20), and 1 year or less on HAART (OR = 11.11, 95% CI: 5.00 to 25.00). Modification was associated with more than 3 months' duration on HAART (OR = 3.13, 95% CI: 1.16 to 8.33) and being unmarried (OR = 1.64, 95% CI: 1.02 to 2.70). The proportions of discontinuation and modification of antiretroviral therapy (ART) observed in our resource-poor setting pose a challenge to the limited treatment options presently available. Drug cost as a major reason for discontinuation of HAART has major implications for ART programs that charge fees in resource-limited settings.

PLOS One, 2010

Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribut... more Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Aids, 2007

To measure nevirapine elimination in African adults undertaking a structured treatment interrupti... more To measure nevirapine elimination in African adults undertaking a structured treatment interruption (STI) in the DART trial. Cohort (16 women, 5 men; median weight 61 kg) within a randomized trial of management strategies. Plasma nevirapine was measured by validated high performance liquid chromatography at 0,1,2,3 and 4 weeks after stopping the drug in a subset of patients undertaking an STI. All patients continued lamivudine plus zidovudine/stavudine for a further 7 days. Two patients with no or low plasma nevirapine concentration at baseline were excluded. Geometric mean plasma concentration when nevirapine was stopped in the remaining 19 patients was 6421 ng/ml (range, 3724-9473). Nevirapine was detected in 15/18 (83%) patients at 1 week, and 5/19 (26%) patients at 2 weeks but was not found any samples collected after 2 weeks. Only one patient had > 100 ng/ml (limit of quantification) at 2 weeks (415 ng/ml, female). The median times to reach thresholds of 200, 100 and 20 ng/ml (limit of detection) were estimated to be 7.6 [interquartile range (IQR), 7.0-10.1], 9.3 (IQR, 8.7-13.0) and 13.2 (IQR, 12.3-18.4) days, respectively, with 3/19 (16%) and 14/19 (74%) estimated to have reached < 20 ng/ml by 7 and 14 days, respectively. Although elimination of nevirapine was faster than previously published after a single dose, the data suggest that an additional staggered period of 7-10 days with dual nucleotide reverse transcriptase inhibitor cover is necessary for African patients discontinuing nevirapine.

Jaids-journal of Acquired Immune Deficiency Syndromes, 2008

Good adherence is essential for successful antiretroviral therapy (ART) provision, but simple mea... more Good adherence is essential for successful antiretroviral therapy (ART) provision, but simple measures have rarely been validated in Africa. This was an observational analysis of an open multicenter randomized HIV/AIDS management trial in Uganda and Zimbabwe. At 4-weekly clinic visits, ART drugs were provided and adherence measured through pill usage and questionnaire. Viral load response was assessed in a subset of patients. Drug possession ratio (percentage of drugs taken between visits) defined complete (100%) and good (>or=95%) adherence. In 2,957 patients, 90% had pill counts at every visit. Good adherence increased from 87%, 4 weeks after ART initiation, to 94% at 48 weeks, but only 1,454 (49%) patients achieved good adherence at every visit in the first year. Complete adherence was associated with 0.32 greater reduction in log10 viral load (95% confidence interval 0.05, 0.60 P = 0.02) and was independently associated with higher baseline CD4 count, starting ART later in the trial, reporting a single regular sexual partner, clinical center, and time on ART. Population level adherence improved over time suggesting an association with clinical experience. Most patients had at least one visit in the year on which they reported not having good adherence, showing the need for continued adherence interventions.

PLOS One, 2010

Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribut... more Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Aids Research and Human Retroviruses, 2006

Cytolytic T lymphocytes (CTL) play an important role in the control of HIV infection. The eventua... more Cytolytic T lymphocytes (CTL) play an important role in the control of HIV infection. The eventual failure to contain HIV-1 infection may arise because of a functional impairment of HIV-specific CTL. We evaluated Gag-specific cytotoxicity in HIV-1-positive Ugandans. Expression of CD107, a marker for cytolytic activity, was present in CD45RA(bright) and CD45RA(dim) CD8(+) T cell populations in HIV-infected individuals. The frequency of Gag-specific CD107(+)CD45RA(bright)CD28(-)CCR7(-) CD8(+) T cells decreased with CD4 cell depletion and correlated with the presence of Gag-specific T helper response. In contrast, the frequency of Gag-specific CD107(+)CD45RA(dim)CD28(-)CCR7(-) CD8(+) T cells within the same individuals has no significant association with viral load or CD4 cell count. The ratio of CD45RA(bright) to CD45RA(dim) CTL correlates significantly with CD4 cell count. This positive association decreases with antiretroviral treatment (ARV), indicating that suppression of viral replication alters the balance of circulating Gag-specific CD8(+) effector T cells. Subsets of cytolytic T cells may have distinct antiviral functions and further characterization of these effector CD8(+) T cells may yield important information on T cell regulation and dysfunction in HIV infection.

Hiv Medicine, 2010

Background Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-li... more Background Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa.Methods A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/μL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat.Results The median pre-ART CD4 count was 99 cells/μL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/μL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24–1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34–1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46–0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001).Conclusions The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Vaccine, 2008

The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus ... more The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus (HIV)-infected adults because of non-functional antibodies. 58 HIV-1-infected and 29 HIV-uninfected Ugandan adults were immunized with conjugate vaccine (CV) followed by polysaccharide vaccine (PV) after a 2-month interval, and the opsonophagocytic killing (OPK) titers against serotype 4 or 14 pneumococcal strains as well as the levels of serotype-specific IgG in sera were determined. Significant increases were found in the OPK titers and IgG levels for both serotypes after CV vaccination irrespective of HIV status. Increases in IgG levels and OPK titers were largely dependent on the CD4(+) cell counts, except for increases in the IgG levels for serotype 4. The proportions with serum OPK titer equal to or greater than 8 were 0-4.3% for serotype 4 and 26.7-42.9% for serotype 14 before vaccination, but the proportions increased up to 43.3-86.2% for serotype 4 and 63.3-96.6% for serotype 14 in all three groups 2 months after CV vaccination. The serum OPK titers remained at levels higher than the pre-vaccination level for at least 8 months after CV vaccination. A single dose of CV could afford some protective immunity in HIV-infected African adults before the introduction of antiretroviral therapy.

PLOS One, 2011

Introduction: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settin... more Introduction: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settings to represent the gold standard of CD4 counts for antiviral therapy initiation. The utility of the WHO-defined stage 1 and 2 clinical factors used in WHO HIV/AIDS clinical staging in predicting low CD4 cell count has not been established in Uganda. Although the WHO staging has shown low sensitivity for predicting CD4,200cells/mm 3 , it has not been evaluated at for CD4 cut-offs of ,250cells/mm 3 or ,350 cells/mm 3 .

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Tropical Medicine & International Health, 2002

OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Ugan... more OBJ ECTIVE To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS METHO DS We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrolment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days.

Host immunity plays an important role in response to antimalarial therapy but is poorly understoo... more Host immunity plays an important role in response to antimalarial therapy but is poorly understood. To test whether T cell activation is a risk factor for antimalarial treatment failure, we studied CD4 + and CD8 + T cell activation in 31 human immunodeficiency virus-negative Ugandan patients 5-37 years of age who were treated for uncomplicated Plasmodium falciparum malaria. Increased CD4 + T cell activation, as indicated by co-expression of HLA-DR and CD38, was an independent risk factor for treatment failure (hazard ratio ‫ס‬ 2.45, 95% confidence interval ‫ס‬ 1.02-5.89, P ‫ס‬ 0.05) in multivariate analysis controlling for age, baseline temperature, and pre-treatment parasite density. The results provide insight into the role of cellular immunity in response to antimalarial therapy and underscore the need to investigate the mechanisms behind immune activation.

Antimicrobial Agents and Chemotherapy, 2010

/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a d... more /150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n ‫؍‬ 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n ‫؍‬ 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n ‫؍‬ 20), nevirapine (n ‫؍‬ 18), and no NNRTI (n ‫؍‬ 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC 0-12 ) was 110.1 (34%) g ⅐ h/liter. For efavirenz, the geometric mean lopinavir AUC 0-12 (%CV) values were 91.8 g ⅐ h/liter (58%), 65.7 g ⅐ h/liter (39%), and 54.0 g ⅐ h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P ‫؍‬ 0.002) and 0.82 (90% CI, 0.68 to 0.99; P ‫؍‬ 0.09),

Journal of The International Aids Society, 2008

With NNRTI, the recommended dose of lopinavir/r (LPV/ r) is 4 capsules (533/133 mg) BD. With LPV/... more With NNRTI, the recommended dose of lopinavir/r (LPV/ r) is 4 capsules (533/133 mg) BD. With LPV/r tablets, the closest doses are 2 tablets (400/100 mg) BD or 3 tablets [tabs] (600/150 mg) BD. Improved bioavailability of the tablet suggests that 2 tabs BD should be sufficient, but PK data are few and generally from Caucasians.

Lancet, 2010

Background-Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa... more Background-Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults.

Journal of The International Association of Physicians in Aids Care (jiapac), 2007

Aids Research and Human Retroviruses, 2009

We set out to investigate whether there are clinically significant consequences when children wit... more We set out to investigate whether there are clinically significant consequences when children with perinatal exposure to single-dose nevirapine are initiated on a nonnucleoside reverse transcriptase inhibitor (NNRTI) containing a highly active antiretroviral therapy (HAART) regimen. We carried out a chart and database review of 104 HIV-infected children, who had initiated HAART with an NNRTI at JCRC and were less than or equal to 5 years of age, 35 (33.7%) of whom had prior exposure to perinatal single-dose nevirapine. We studied the viral load and CD4 percentage at baseline, at week 24, and at week 48 after the start of HAART in children exposed and not exposed to perinatal single-dose nevirapine, as well as the results of genotypic resistance testing done for the children who had failed to achieve virologic suppression on HAART. At weeks 24 and 48 after initiating HAART, children not exposed to single-dose nevirapine were 3.28 times [OR = 3.28, 95% CI: (1.37 to 9.20), p = 0.0167] and 3.47 times [OR = 3.47, 95% CI: (1.28 to 9.37), p = 0.0091] more likely to achieve virologic suppression compared to children exposed to single-dose nevirapine, respectively. However, the CD4 cell response at weeks 24 and 48 was not worse in the children exposed to single-dose nevirapine. In 10 children with perinatal exposure to single-dose nevirapine, NNRTI resistance mutations, mostly K103N, Y181C, and G109A, were identified. HIV-infected children with perinatal exposure to single-dose nevirapine are less likely to achieve short-term virologic suppression when started on an NNRTI-containing regimen, when compared to those who were not exposed to it, probably because the exposure predisposes them to developing NNRTI resistance mutations.

Aids, 2007

... J Infect Dis 2006; 193:1195–1201. 4. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG... more ... J Infect Dis 2006; 193:1195–1201. 4. Schulte J, Dominguez K, Sukalac T, Bohannon B, Fowler MG. ... Victor Musiime, Francis Ssali, Hilda Kizito, Cissy Kityo and Peter Mugyenyi, Joint Clinical Research Centre, Kampala, Uganda. ...

Jaids-journal of Acquired Immune Deficiency Syndromes, 2007

Data on discontinuation and modification of highly active antiretroviral therapy (HAART) are scar... more Data on discontinuation and modification of highly active antiretroviral therapy (HAART) are scarce among sub-Saharan African populations. We sought to estimate the prevalence and to identify factors associated with these phenomena in our resource-limited setting. Patients were recruited into this cross-sectional study from 2 treatment centers in Kampala, Uganda. Discontinuation and modification were assessed by self-report using semistructured quantitative and unstructured qualitative interviews. Discontinuation was defined as the simultaneous stopping of all antiretrovirals for at least 1 month, and modification as the changing of at least 1 antiretroviral used in an initial HAART regimen. Factors independently associated with each outcome were assessed using multivariate logistic regression. Of 686 subjects evaluated, 94 (13.7%) had ever discontinued therapy, whereas 175 (25.5%) had ever modified their regimen. The median CD4 count was 175 (interquartile range: 66-297) cells/microL. Factors associated with discontinuation were HAART experience before starting the current regimen (odds ratio [OR] = 3.70, 95% confidence interval [CI]: 2.13 to 6.25), use of alternative medicines (OR = 2.18, 95% CI: 1.06 to 4.47), hospitalization (OR = 2.36, 95% CI: 1.32 to 4.20), and 1 year or less on HAART (OR = 11.11, 95% CI: 5.00 to 25.00). Modification was associated with more than 3 months&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; duration on HAART (OR = 3.13, 95% CI: 1.16 to 8.33) and being unmarried (OR = 1.64, 95% CI: 1.02 to 2.70). The proportions of discontinuation and modification of antiretroviral therapy (ART) observed in our resource-poor setting pose a challenge to the limited treatment options presently available. Drug cost as a major reason for discontinuation of HAART has major implications for ART programs that charge fees in resource-limited settings.

PLOS One, 2010

Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribut... more Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Aids, 2007

To measure nevirapine elimination in African adults undertaking a structured treatment interrupti... more To measure nevirapine elimination in African adults undertaking a structured treatment interruption (STI) in the DART trial. Cohort (16 women, 5 men; median weight 61 kg) within a randomized trial of management strategies. Plasma nevirapine was measured by validated high performance liquid chromatography at 0,1,2,3 and 4 weeks after stopping the drug in a subset of patients undertaking an STI. All patients continued lamivudine plus zidovudine/stavudine for a further 7 days. Two patients with no or low plasma nevirapine concentration at baseline were excluded. Geometric mean plasma concentration when nevirapine was stopped in the remaining 19 patients was 6421 ng/ml (range, 3724-9473). Nevirapine was detected in 15/18 (83%) patients at 1 week, and 5/19 (26%) patients at 2 weeks but was not found any samples collected after 2 weeks. Only one patient had &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 100 ng/ml (limit of quantification) at 2 weeks (415 ng/ml, female). The median times to reach thresholds of 200, 100 and 20 ng/ml (limit of detection) were estimated to be 7.6 [interquartile range (IQR), 7.0-10.1], 9.3 (IQR, 8.7-13.0) and 13.2 (IQR, 12.3-18.4) days, respectively, with 3/19 (16%) and 14/19 (74%) estimated to have reached &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 20 ng/ml by 7 and 14 days, respectively. Although elimination of nevirapine was faster than previously published after a single dose, the data suggest that an additional staggered period of 7-10 days with dual nucleotide reverse transcriptase inhibitor cover is necessary for African patients discontinuing nevirapine.

Jaids-journal of Acquired Immune Deficiency Syndromes, 2008

Good adherence is essential for successful antiretroviral therapy (ART) provision, but simple mea... more Good adherence is essential for successful antiretroviral therapy (ART) provision, but simple measures have rarely been validated in Africa. This was an observational analysis of an open multicenter randomized HIV/AIDS management trial in Uganda and Zimbabwe. At 4-weekly clinic visits, ART drugs were provided and adherence measured through pill usage and questionnaire. Viral load response was assessed in a subset of patients. Drug possession ratio (percentage of drugs taken between visits) defined complete (100%) and good (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=95%) adherence. In 2,957 patients, 90% had pill counts at every visit. Good adherence increased from 87%, 4 weeks after ART initiation, to 94% at 48 weeks, but only 1,454 (49%) patients achieved good adherence at every visit in the first year. Complete adherence was associated with 0.32 greater reduction in log10 viral load (95% confidence interval 0.05, 0.60 P = 0.02) and was independently associated with higher baseline CD4 count, starting ART later in the trial, reporting a single regular sexual partner, clinical center, and time on ART. Population level adherence improved over time suggesting an association with clinical experience. Most patients had at least one visit in the year on which they reported not having good adherence, showing the need for continued adherence interventions.

PLOS One, 2010

Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribut... more Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Aids Research and Human Retroviruses, 2006

Cytolytic T lymphocytes (CTL) play an important role in the control of HIV infection. The eventua... more Cytolytic T lymphocytes (CTL) play an important role in the control of HIV infection. The eventual failure to contain HIV-1 infection may arise because of a functional impairment of HIV-specific CTL. We evaluated Gag-specific cytotoxicity in HIV-1-positive Ugandans. Expression of CD107, a marker for cytolytic activity, was present in CD45RA(bright) and CD45RA(dim) CD8(+) T cell populations in HIV-infected individuals. The frequency of Gag-specific CD107(+)CD45RA(bright)CD28(-)CCR7(-) CD8(+) T cells decreased with CD4 cell depletion and correlated with the presence of Gag-specific T helper response. In contrast, the frequency of Gag-specific CD107(+)CD45RA(dim)CD28(-)CCR7(-) CD8(+) T cells within the same individuals has no significant association with viral load or CD4 cell count. The ratio of CD45RA(bright) to CD45RA(dim) CTL correlates significantly with CD4 cell count. This positive association decreases with antiretroviral treatment (ARV), indicating that suppression of viral replication alters the balance of circulating Gag-specific CD8(+) effector T cells. Subsets of cytolytic T cells may have distinct antiviral functions and further characterization of these effector CD8(+) T cells may yield important information on T cell regulation and dysfunction in HIV infection.

Hiv Medicine, 2010

Background Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-li... more Background Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa.Methods A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/μL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat.Results The median pre-ART CD4 count was 99 cells/μL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/μL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24–1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34–1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46–0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001).Conclusions The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Vaccine, 2008

The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus ... more The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus (HIV)-infected adults because of non-functional antibodies. 58 HIV-1-infected and 29 HIV-uninfected Ugandan adults were immunized with conjugate vaccine (CV) followed by polysaccharide vaccine (PV) after a 2-month interval, and the opsonophagocytic killing (OPK) titers against serotype 4 or 14 pneumococcal strains as well as the levels of serotype-specific IgG in sera were determined. Significant increases were found in the OPK titers and IgG levels for both serotypes after CV vaccination irrespective of HIV status. Increases in IgG levels and OPK titers were largely dependent on the CD4(+) cell counts, except for increases in the IgG levels for serotype 4. The proportions with serum OPK titer equal to or greater than 8 were 0-4.3% for serotype 4 and 26.7-42.9% for serotype 14 before vaccination, but the proportions increased up to 43.3-86.2% for serotype 4 and 63.3-96.6% for serotype 14 in all three groups 2 months after CV vaccination. The serum OPK titers remained at levels higher than the pre-vaccination level for at least 8 months after CV vaccination. A single dose of CV could afford some protective immunity in HIV-infected African adults before the introduction of antiretroviral therapy.

PLOS One, 2011

Introduction: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settin... more Introduction: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settings to represent the gold standard of CD4 counts for antiviral therapy initiation. The utility of the WHO-defined stage 1 and 2 clinical factors used in WHO HIV/AIDS clinical staging in predicting low CD4 cell count has not been established in Uganda. Although the WHO staging has shown low sensitivity for predicting CD4,200cells/mm 3 , it has not been evaluated at for CD4 cut-offs of ,250cells/mm 3 or ,350 cells/mm 3 .