Research papers (Caprisa)

Permanent URI for this collectionhttps://hdl.handle.net/10413/7816

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Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.
(American Association of Immunologists., 2015) Scheepers, Cathrine.; Shrestha, Ram K.; Lambson, Bronwen Elizabeth.; Jackson, Katherine J. L.; Wright, Imogen A.; Naicker, Dshanta Dyanedi.; Goosen, Mark.; Berrie, Leigh.; Ismail, Arshad.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Moore, Penelope L.; Travers, Simon A.; Morris, Lynn.
Abstract available in pdf.
Acceptability of early antiretroviral therapy among South African women.
(Springer., 2018) Garrett, Nigel Joel.; Norman, Emily.; Leask, Kerry.; Naicker, Nivashnee.; Asari, Villeshni.; Majola, Nelisile.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Achieving the health Millennium Development Goals for South Africa : challenges and priorities.
(Elsevier., 2009) Chopra, Mickey.; Lawn, Joy E.; Sanders, David.; Barron, Peter.; Abdool Karim, Salim Safurdeen.; Bradshaw, Debbie.; Jewkes, Rachel.; Abdool Karim, Quarraisha.; Flisher, Alan J.; Mayosi, Bongani M.; Tollman, Stephen M.; Churchyard, Gavin J.; Coovadia, Hoosen Mahomed.
15 years after liberation from apartheid, South Africans are facing new challenges for which the highest calibre of leadership, vision, and commitment is needed. The effect of the unprecedented HIV/AIDS epidemic has been immense. Substantial increases in mortality and morbidity are threatening to overwhelm the health system and undermine the potential of South Africa to attain the Millennium Development Goals (MDGs). However The Lancet’s Series on South Africa has identified several examples of leadership and innovation that point towards a different future scenario. We discuss the type of vision, leadership, and priority actions needed to achieve such a change. We still have time to change the health trajectory of the country, and even meet the MDGs. The South African Government, installed in April, 2009, has the mandate and potential to address the public health emergencies facing the country—will they do so or will another opportunity and many more lives be lost?
Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure.
(Elsevier., 2009) Treurnicht, Florette K.; Seoighe, Cathal.; Martin, Darren Patrick.; Wood, N.; Abrahams, Melissa-Rose.; de Assis Rosa, Debra.; Bredell, Helba.; Woodman, Zenda.; Hide, Winston.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential “transmission signatures”, we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission.
An adaptive design to bridge the gap between phase 2b/3 microbicide effectiveness trials and evidence required for licensure.
(Sage., 2012) Taylor, Douglas.; Grobler, Anna Christina.; Abdool Karim, Salim Safurdeen.
Background. Vaginally and rectally applied microbicides are being developed to help prevent sexual acquisition of HIV. Due to the lack of surrogate outcomes, the path toward licensure typically moves directly from expanded safety studies to expensive Phase 2b/3 trials with rare incident infection outcomes. The need to confirm an initial trial’s significant finding can lead to serious delays in implementing essential programs to reduce the spread of HIV. Purpose. To propose an adaptive design where a Phase 2b/3 study powered to detect a clinically meaningful effect with evidence of one trial (observing one-sided p < 0.025) is allowed to expand by a prespecified, feasible amount if interim data suggest the chance of further achieving a more robust evidence threshold ( p < 0.001, potentially sufficient for licensure from a single trial) is promising. Methods. As an example, prespecified conditional power criteria are used to determine whether a 90-event trial with 90% power to detect a 50% reduction in risk should be expanded to 130 events. Asymptotic results and simulations are used to assess false-positive error rates and other operating characteristics of the design. Results. False-positive error rates can be controlled at the desired 0.025 and 0.001 levels with appropriate choice of critical values or expansion criteria. The chance of achieving robust evidence can approach that of a 130-event trial with traditional stopping boundaries (controlling a = 0.001) but with substantially lower expected size for plausible effectiveness levels. Limitations. Conditional power calculations assume the interim estimate of effect is an unbiased estimate for the remainder of the trial, an assumption which may not hold if product adherence varies over time. Observing a measure of effect with p < 0.001 may not be sufficient for licensure. A decision to expand the trial would be informative to investigators regarding the interim effect size. Conclusions. A moderate increase in trial size can make the difference between a study with good power to detect a clinically meaningful effect and one which may reasonably obtain the robust evidence required for regulatory bodies and public health programs to consider making a new microbicide available to persons at risk of HIV infection. The proposed design allows for this possibility while not requiring investigators to make an up-front commitment to a prohibitively large trial.
Addressing challenges in scaling up TB and HIV treatment integration in rural primary healthcare clinics in South Africa (SUTHI): a cluster randomized controlled trial protocol.
(Implementation Science., 2015) Naidoo, Kogieleum.; Gengiah, Santhanalakshmi.; Yende-Zuma, Fortunate Nonhlanhla.; Padayatchi, Nesri.; Barker, Pierre.; Nunn, Andrew.; Subrayen, Priashni.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Adherence in the CAPRISA 004 tenofovir gel microbicide trial.
(Springer., 2014) Mansoor, Leila Essop.; Abdool Karim, Quarraisha.; Yende-Zuma, Fortunate Nonhlanhla.; MacQueen, Kathleen M.; Baxter, Cheryl.; Madlala, Bernadette T.; Grobler, Anneke.; Abdool Karim, Salim Safurdeen.
High adherence is key to microbicide effectiveness. Here we provide a description of adherence interventions and the adherence rates achieved in the CAPRISA 004 Tenofovir Gel Trial. Adherence support for the before-and-after dosing strategy (BAT 24) was provided at enrolment and at each monthly study visit. This initially comprised individual counselling and was replaced midway by a structured theory-based adherence support program (ASP) based on motivational interviewing. The 889 women were followed for an average of 18 months and attended a total of 17031 monthly visits. On average women reported 5 sex acts and returned 5.9 empty applicators per month. The adherence rate based on applicator count in relation to all reported sex acts was 72.2% compared to the 82.0% self-reported adherence during the last sex act. Adherence support activities, which achieve levels of adherence similar to or better than those achieved by the CAPRISA 004 ASP, will be critical to the success of future microbicide trials.
An AIDS-Free Generation?
(American Association for the Advancement of Science., 2012) Abdool Karim, Salim Safurdeen.
No abstract available.
Amino acid changes in the HIV-1 gp41 membrane proximal region control virus neutralization sensitivity.
(Elsevier., 2016) Bradley, Todd.; Trama, Ashley.; Tumba, Nancy Lola.; Gray, Elin Solomonovna.; Lu, Xiaozhi.; Madani, Navid.; Jahanbakhsh, Fatemeh.; Eaton, Amanda.; Xia, Shi-Mao.; Parks, Robert.; Lloyd, Krissey E.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Barnett, Susan.; Abdool Karim, Salim Safurdeen.; Boyd, Scott D.; Melillo, Bruno.; Smith, Amos B.; Sodroski, Joseph.; Kepler, Thomas B.; Alam, Shabnam Munir.; Gao, Feng.; Bonsignori, Mattia.; Liao, Hua-Xin.; Moody, Michael Anthony.; Montefiori, David Charles.; Santra, Sampa.; Morris, Lynn.; Haynes, Barton F.
Abstract available in pdf.
Anaemia in acute HIV-1 Subtype C infection.
(Plos., 2007) Mlisana, Koleka Patience.; Auld, Sara C.; Grobler, Anna Christina.; van Loggerenberg, Francois.; Williamson, Carolyn.; Iriogbe, Itua.; Sobieszczyk, Magdalena E.; Abdool Karim, Salim Safurdeen.
Background: The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection. Methods: HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection. Results: Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10– 81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15–104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months postinfection, and 51.4% at 12 months post-infection. Conclusions: Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown.
Antibodies for HIV prevention in young women.
(Wolters Kluwer., 2015) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Baxter, Cheryl.
Abstract available.
Antibody maturation in women who acquire HIV infection while using antiretroviral pre-exposure prophylaxis.
(Oxford University Press., 2015) Laeyendecker, Oliver.; Redd, Andrew D.; Nason, Martha.; Longosz, Andrew F.; Abdool Karim, Quarraisha.; Naranbhai, Vivek.; Garrett, Nigel Joel.; Eshleman, Susan H.; Abdool Karim, Salim Safurdeen.; Quinn, Thomas C.
Abstract available in pdf.
Antiretroviral prophylaxis for HIV prevention reaches a key milestone.
(Elsevier., 2012) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.
No abstract available.
Antiretroviral prophylaxis: a defining moment in HIV control.
(Elsevier., 2011) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.
No abstract available.
Antiretroviral therapy : challenges and options in South Africa.
(Elsevier., 2003) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Baxter, Cheryl.
No abstract available.
APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4R T-cell counts and plasma viral load.
(Lippincott Williams & Wilkins., 2008) Reddy, Kavidha.; Winkler, Cheryl Ann.; Werner, Lise.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.
Objectives: In the absence of HIV-1 virion infectivity factor (Vif), cellular cytosine deaminases such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4+ T-cell counts as outcomes. Methods: Study participants were 250 South African women at high risk for HIV-1 subtype C infection.We used real-time PCR to measure the expression of APOBEC3G in HIV-negative and HIV-positive primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping. Results: We found no correlation between APOBEC3G expression levels and plasma viral loads (r=0.053, P=0.596) or CD4+ T-cell counts (r=0.030, P=0.762) in 32 seroconverters. APOBEC3G expression levels were higher in HIV-negative individuals as compared with HIV-positive individuals (P<0.0001), including matched pre and postinfection samples from the same individuals (n=13, P<0.0001). Twenty-four single nucleotide polymorphisms, including eight novel, were identified within APOBEC3G by re-sequencing and genotyping. The H186R mutation, a codon-changing variant in exon 4, and a 3' extragenic mutation (rs35228531) were associated with high viral loads (P=0.0097 and P<0.0001) and decreased CD4+ T-cell levels (P=0.0081 and P<0.0001), respectively. Conclusion: These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G expression levels in peripheral blood mononuclear cells do not correlate with viral loads or CD4+ T-cell counts. Genetic variation of APOBEC3G may significantly affect early HIV-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
Assessing adherence in the CAPRISA 004 tenofovir gel HIV prevention trial: results of a nested case–control study.
(Springer., 2014) MacQueen, Kathleen M.; Weaver, Mark A.; van Loggerenberg, Francois.; Succop, Stacey M.; Majola, Nelisile.; Taylor, Douglas.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Assessing progress with HIV incidence in national cohorts.
(Elsevier., 2017) Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial.
(BioMed Central., 2014) Mansoor, Leila Essop.; Abdool Karim, Quarraisha.; Mngadi, Kathryn Therese.; Dlamini, Sarah Alexandra.; Montague, Carl.; Nkomonde, Nelisiwe.; Mvandaba, Nomzamo.; Baxter, Cheryl.; Gengiah, Tanuja Narayansamy.; Samsunder, Natasha.; Dawood, Halima.; Grobler, Anna Christina.; Fröhlich, Janet Ann.; Abdool Karim, Salim Safurdeen.
Background: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. Methods/design: This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. Discussion: This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. Trial registration: This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.
Association of HIV-Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point.
(The American Association of Immunologists, Inc., 2009) Burgers, Wendy A.; Riou, Catherine.; Mlotshwa, Mandla.; Maenetje, Pholo.; de Assis Rosa, Debra.; Brenchley, Jason.; Mlisana, Koleka Patience.; Douek, Daniel C.; Koup, Richard A.; Roederer, Mario.; De Bruyn, Guy.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Gray, Clive M.
Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8+ T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-γ+ T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8+ T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8+ memory subpopulations. At 6–9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8+ cells of a central memory (CD45RO+CD27+CCR7+) and intermediate memory (CD45RO−CD27+CCR7−) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO+CD27−CCR7−) cells. The proportions of memory subsets significantly correlated with CD38+CD8+ T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8+ T cells.

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Browsing Research papers (Caprisa) by Author "Abdool Karim, Salim Safurdeen."