The safety, immunologic, and antiviral effects of a recombinant biologic product that combines th... more The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
Despite rapid expansion of antiretroviral therapy (ART) in sub-Saharan Africa there are few longi... more Despite rapid expansion of antiretroviral therapy (ART) in sub-Saharan Africa there are few longitudinal data describing programme performance during rapid scale-up. We compared mortality, viral suppression and programme retention in 3 consecutive years of a public sector community-based ART clinic in a South African township. Data were collected prospectively from establishment of services in October 2002 to the censoring date in September 2005. Viral load and CD4 counts were monitored at 4-monthly intervals. Community-based counsellors provided adherence and programme support. During the study period 1139 ART-naïve patients received ART (161, 280 and 698 in the 1st, 2nd and 3rd years respectively). The median CD4 cell counts were 84 cells/microl (interquartile range (IQR) 42-139), 89 cells/microl (IQR 490-149), and 110 cells/microl (IQR 55-172), and the proportions of patients with World Health Organization (WHO) clinical stages 3 and 4 were 90%, 79% and 76% in each sequential yea...
Background This study aimed to evaluate HIV type-1 (HIV-1) drug resistance pretreatment and in th... more Background This study aimed to evaluate HIV type-1 (HIV-1) drug resistance pretreatment and in those failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) in South Africa. Methods This was an observational cohort. Genotypic resistance testing was performed on treatment-naive individuals and those failing first-line ART (confirmed HIV-1 RNA>1,000 copies/ml) from public sector clinics in Cape Town (2002–2007). Resistance profiles and mutations relative to timing of known virological failure were examined. Results In total, 230 patients (120 treatment-naive and 110 with virological failure) were included: 98% had clade C virus. Among treatment-naive patients, prevalence of primary resistance was 2.5% (95% confidence interval 0.0–5.3). Three patients had one significant reverse transcriptase mutation: K65R, Y181C and G190A. Among treatment-experienced patients, 95 (86%) individuals had therapy-limiting NNRTI mutations, including ...
BackgroundReports of a single case of human immunodeficiency virus (HIV) eradication suggest that... more BackgroundReports of a single case of human immunodeficiency virus (HIV) eradication suggest that elimination of HIV from individuals is possible. Anticipating both increased research funding and the development of effective, durable cure technologies, we describe the circumstances under which a cure might improve survival and be cost-effective in South Africa.MethodsWe adapted a simulation model comparing a hypothetical cure strategy (“Cure”) to the standard of care, lifetime antiretroviral therapy (“LifetimeART”) among adherent South Africans (58% female; mean age 33.8 years; mean CD4 257/µL; virologic suppression ≥1 year). We portrayed cure as a single intervention, producing sustained viral eradication without ART. We considered both a plausible, more imminently achievable “Baseline Scenario” and a more aspirational “Optimistic Scenario”. Inputs (Baseline/Optimistic) included the following: 50%/75% efficacy; 0.6%/0.0% fatal toxicity; 0.37%/0.085% monthly relapse over 5 years (0....
Background: With increased enrollment and time spent on ART in resource-limited settings, more AR... more Background: With increased enrollment and time spent on ART in resource-limited settings, more ART-recipients may face virologic failure on 1st-line and require 2nd-line regimens. However, there are few reports on 2nd-line ART effectiveness and factors related to virologic suppression in community-based settings in South Africa. Methods: We analyzed data on patients switched to 2nd-line ART consisting of AZT, ddi, and LPV/r (national treatment guidelines) in a community-based ART program in a Cape Town township. We focused on 24-week virologic suppression (HIV RNA <400 copies/ml) on 2nd-line. We conducted both an “intent to treat (ITT)” analysis, assuming that those with missing data were not suppressed, and an “as-treated” analysis where we excluded missing data. We examined whether early (≤ 90 days) or late (> 90 days) switching after virologic failure (2 consecutive HIV RNA >1000 copies/ml) affected 24-week virologic suppression on 2nd-line ART. Results: Of 2,603 patient...
Infection with human immunodeficiency virus (HIV) is found to increase the occurrence of drug res... more Infection with human immunodeficiency virus (HIV) is found to increase the occurrence of drug resistant tuberculosis. The data for HIV and multidrug resistant tuberculosis (MDR-TB) coinfection is scarce in India. The study aims to find out the prevalence of MDR-TB and extensively drug resistant tuberculosis (XDR-TB) among chronic TB patients and to identify their trend with HIV coinfection over time. Non-responding chronic pulmonary tuberculosis patients were selected for the study from 2004 to 2007. They were all subjected to HIV screening and drug susceptibility testing (DST) for anti-TB drugs. In all 2927 chronic tuberculosis patients were assessed for DST and HIV coinfection; 2156 patients (73.7%) had culturable Mycobacterium tuberculosis in their sputum specimens; 1651 patients (56.4%) were found to have drug resistant mutants to one or more anti-TB drugs; 993 patients (33.9%) had MDR-TB and 48 (1.6%) had XDR-TB. Significantly, 17.9% of 1651 patients with drug resistance were f...
Background More patients in resource-limited settings are starting second-line antiretroviral tre... more Background More patients in resource-limited settings are starting second-line antiretroviral treatment (ART) following first-line ART failure. We aimed to describe predictors of lack of virological suppression in HIV-infected patients on second-line ART in a roll-out programme in South Africa. Methods A retrospective analysis was performed on an adult HIV treatment cohort who started second-line ART (lopinavir/ritonavir, didanosine and zidovudine) after virological failure of first-line ART (two consecutive HIV RNA>1,000 copies/ml). Predictors of week 24 lack of suppression (HIV RNA>400 copies/ml) on second-line ART were determined by bivariate analysis where missing equals failure. A multivariable model that adjusted for gender, age and time to ART switch was used. We tested these findings in sensitivity analyses defining lack of suppression at week 24 as HIV RNA>1,000 and >5,000 copies/ml. Results Of 6,339 patients on ART, 202 started second-line ART. At week 24, an e...
levels of soluble urokinase-type plasminogen activator receptor (su-PAR) and early mortality risk... more levels of soluble urokinase-type plasminogen activator receptor (su-PAR) and early mortality risk among patients enrolling for antiretro-viral treatment in South Africa. Bmc Infectious Diseases, 7. ISSN
The tuberculosis (TB) pandemic demands urgent interventions such as those designed to interrupt M... more The tuberculosis (TB) pandemic demands urgent interventions such as those designed to interrupt Mycobacterium tuberculosis (Mtb) transmission, a challenge exacerbated by our poor understanding of the events enabling successful transfer of infectious bacilli between hosts. To address this problem, we developed the Respiratory Aerosol Sampling Chamber (RASC), a personal clean-room equipped with high-efficiency filtration and sampling technologies that allow biosafe capture and isolation of particulate matter – including Mtb bacilli – released by patients during natural breathing and (non-induced) cough. Here, we demonstrate the use of DMN-trehalose labelling to detect and quantify live Mtb bacilli among complex bioaerosol samples arrayed in a bespoke nanowell device following capture in the RASC. A pilot study identified Mtb in more than 85 % of known TB patients, improving significantly on previous work which has relied on animal infection and cough sampling to estimate transmission ...
The safety, immunologic, and antiviral effects of a recombinant biologic product that combines th... more The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
Despite rapid expansion of antiretroviral therapy (ART) in sub-Saharan Africa there are few longi... more Despite rapid expansion of antiretroviral therapy (ART) in sub-Saharan Africa there are few longitudinal data describing programme performance during rapid scale-up. We compared mortality, viral suppression and programme retention in 3 consecutive years of a public sector community-based ART clinic in a South African township. Data were collected prospectively from establishment of services in October 2002 to the censoring date in September 2005. Viral load and CD4 counts were monitored at 4-monthly intervals. Community-based counsellors provided adherence and programme support. During the study period 1139 ART-naïve patients received ART (161, 280 and 698 in the 1st, 2nd and 3rd years respectively). The median CD4 cell counts were 84 cells/microl (interquartile range (IQR) 42-139), 89 cells/microl (IQR 490-149), and 110 cells/microl (IQR 55-172), and the proportions of patients with World Health Organization (WHO) clinical stages 3 and 4 were 90%, 79% and 76% in each sequential yea...
Background This study aimed to evaluate HIV type-1 (HIV-1) drug resistance pretreatment and in th... more Background This study aimed to evaluate HIV type-1 (HIV-1) drug resistance pretreatment and in those failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) in South Africa. Methods This was an observational cohort. Genotypic resistance testing was performed on treatment-naive individuals and those failing first-line ART (confirmed HIV-1 RNA>1,000 copies/ml) from public sector clinics in Cape Town (2002–2007). Resistance profiles and mutations relative to timing of known virological failure were examined. Results In total, 230 patients (120 treatment-naive and 110 with virological failure) were included: 98% had clade C virus. Among treatment-naive patients, prevalence of primary resistance was 2.5% (95% confidence interval 0.0–5.3). Three patients had one significant reverse transcriptase mutation: K65R, Y181C and G190A. Among treatment-experienced patients, 95 (86%) individuals had therapy-limiting NNRTI mutations, including ...
BackgroundReports of a single case of human immunodeficiency virus (HIV) eradication suggest that... more BackgroundReports of a single case of human immunodeficiency virus (HIV) eradication suggest that elimination of HIV from individuals is possible. Anticipating both increased research funding and the development of effective, durable cure technologies, we describe the circumstances under which a cure might improve survival and be cost-effective in South Africa.MethodsWe adapted a simulation model comparing a hypothetical cure strategy (“Cure”) to the standard of care, lifetime antiretroviral therapy (“LifetimeART”) among adherent South Africans (58% female; mean age 33.8 years; mean CD4 257/µL; virologic suppression ≥1 year). We portrayed cure as a single intervention, producing sustained viral eradication without ART. We considered both a plausible, more imminently achievable “Baseline Scenario” and a more aspirational “Optimistic Scenario”. Inputs (Baseline/Optimistic) included the following: 50%/75% efficacy; 0.6%/0.0% fatal toxicity; 0.37%/0.085% monthly relapse over 5 years (0....
Background: With increased enrollment and time spent on ART in resource-limited settings, more AR... more Background: With increased enrollment and time spent on ART in resource-limited settings, more ART-recipients may face virologic failure on 1st-line and require 2nd-line regimens. However, there are few reports on 2nd-line ART effectiveness and factors related to virologic suppression in community-based settings in South Africa. Methods: We analyzed data on patients switched to 2nd-line ART consisting of AZT, ddi, and LPV/r (national treatment guidelines) in a community-based ART program in a Cape Town township. We focused on 24-week virologic suppression (HIV RNA <400 copies/ml) on 2nd-line. We conducted both an “intent to treat (ITT)” analysis, assuming that those with missing data were not suppressed, and an “as-treated” analysis where we excluded missing data. We examined whether early (≤ 90 days) or late (> 90 days) switching after virologic failure (2 consecutive HIV RNA >1000 copies/ml) affected 24-week virologic suppression on 2nd-line ART. Results: Of 2,603 patient...
Infection with human immunodeficiency virus (HIV) is found to increase the occurrence of drug res... more Infection with human immunodeficiency virus (HIV) is found to increase the occurrence of drug resistant tuberculosis. The data for HIV and multidrug resistant tuberculosis (MDR-TB) coinfection is scarce in India. The study aims to find out the prevalence of MDR-TB and extensively drug resistant tuberculosis (XDR-TB) among chronic TB patients and to identify their trend with HIV coinfection over time. Non-responding chronic pulmonary tuberculosis patients were selected for the study from 2004 to 2007. They were all subjected to HIV screening and drug susceptibility testing (DST) for anti-TB drugs. In all 2927 chronic tuberculosis patients were assessed for DST and HIV coinfection; 2156 patients (73.7%) had culturable Mycobacterium tuberculosis in their sputum specimens; 1651 patients (56.4%) were found to have drug resistant mutants to one or more anti-TB drugs; 993 patients (33.9%) had MDR-TB and 48 (1.6%) had XDR-TB. Significantly, 17.9% of 1651 patients with drug resistance were f...
Background More patients in resource-limited settings are starting second-line antiretroviral tre... more Background More patients in resource-limited settings are starting second-line antiretroviral treatment (ART) following first-line ART failure. We aimed to describe predictors of lack of virological suppression in HIV-infected patients on second-line ART in a roll-out programme in South Africa. Methods A retrospective analysis was performed on an adult HIV treatment cohort who started second-line ART (lopinavir/ritonavir, didanosine and zidovudine) after virological failure of first-line ART (two consecutive HIV RNA>1,000 copies/ml). Predictors of week 24 lack of suppression (HIV RNA>400 copies/ml) on second-line ART were determined by bivariate analysis where missing equals failure. A multivariable model that adjusted for gender, age and time to ART switch was used. We tested these findings in sensitivity analyses defining lack of suppression at week 24 as HIV RNA>1,000 and >5,000 copies/ml. Results Of 6,339 patients on ART, 202 started second-line ART. At week 24, an e...
levels of soluble urokinase-type plasminogen activator receptor (su-PAR) and early mortality risk... more levels of soluble urokinase-type plasminogen activator receptor (su-PAR) and early mortality risk among patients enrolling for antiretro-viral treatment in South Africa. Bmc Infectious Diseases, 7. ISSN
The tuberculosis (TB) pandemic demands urgent interventions such as those designed to interrupt M... more The tuberculosis (TB) pandemic demands urgent interventions such as those designed to interrupt Mycobacterium tuberculosis (Mtb) transmission, a challenge exacerbated by our poor understanding of the events enabling successful transfer of infectious bacilli between hosts. To address this problem, we developed the Respiratory Aerosol Sampling Chamber (RASC), a personal clean-room equipped with high-efficiency filtration and sampling technologies that allow biosafe capture and isolation of particulate matter – including Mtb bacilli – released by patients during natural breathing and (non-induced) cough. Here, we demonstrate the use of DMN-trehalose labelling to detect and quantify live Mtb bacilli among complex bioaerosol samples arrayed in a bespoke nanowell device following capture in the RASC. A pilot study identified Mtb in more than 85 % of known TB patients, improving significantly on previous work which has relied on animal infection and cough sampling to estimate transmission ...
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