College of Health Sciences

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Challenges in the integration of TB and HIV care : evidence for improving patient management and health care policy.
(2016) Naidoo, Kogieleum.; Abdool Karim, Salim Safurdeen.
TB infection remains a leading cause of morbidity and mortality among patients with HIV infection, while HIV is the strongest risk factor for development of active TB. Integration of HIV and TB treatment is key to reducing mortality in co-infected patients; but many obstacles stand in the way of effective scale-up of this approach to HIV-TB treatment. The challenges associated with HIV-TB integration extend from clinical complexities in individual patient management, to impediments in health service organization and prioritization to address this urgent public health priority, especially in sub-Saharan Africa where TB-HIV co-infection rates reach 80%. The purpose of this study was to assess and identify strategies to overcome the challenges in immune reconstitution and drug safety/tolerability when integrating HIV and TB care in a cost-effective manner to reduce co-infection mortality. Clinical and operational service data from the Starting Antiretroviral therapy at three Points in Tuberculosis Treatment (SAPiT – CAPRISA 003) study, a 3-arm, randomized control trial in 642 newly diagnosed sputum smear-positive TB-HIV co-infected adult patients with screening CD4+ cell count < 500 cells/mm3, were analysed. In addition, the incidence rate of unmasked clinical TB following ART initiation was assessed through a retrospective chart review conducted in HIV infected patients enrolled at the rural CAPRISA AIDS Treatment Programme. Overall, mortality was 56% lower (RR=0.44; 95% CI: 0.25 to 0.79; P = 0.003) in patients initiated on ART during TB treatment compared to ART deferral to after TB treatment completion. However, the risk of immune reconstitution inflammatory syndrome (IRIS) was higher (incidence rate ratio (IRR), 2.6 (95% CI, 1.5 to 4.8); P < 0.001, in patients initiating ART within the first 2 months compared to later ART initiation during TB treatment. In the most severely immuno-compromised patients (CD4 counts <50 cells/mm3) early ART integration was associated with an almost five-fold increased risk of IRIS (IRR 4.7 (95% CI, 1.5 to 19.6); P = 0.004. Patients initiating ART in the first 2 months of TB therapy had higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other two groups. When assessing available evidence, these results indicate that ART initiation in patients with CD4 cell counts >50 cells/mm3 would be most appropriate after completion of intensive phase of TB therapy, a strategy that was found to cost $1840 per patient treated. Among HIV infected patients initially screening negative for TB there was a fourfold higher incidence rate of unmasking TB in the first 3 months after ART initiation, compared to the subsequent 21 months post-ART initiation. The new information generated by this study provides important evidence for policy and clinical management of patients with HIV and TB co-infection. Firstly, careful clinical vigilance for ‘unmasked’ TB is required in patients initiating ART. Secondly, the survival benefit of AIDS therapy in TB patients can be maximized by initiating ART as soon as possible after TB therapy has been started in patients with advanced immunosuppression, i.e., those with CD4+ counts <50 cells/mm3. However, patients with higher CD4+ cell counts should delay ART initiation to at least 8 weeks after the start of TB therapy to minimize the incidence and duration of immune reconstitution disease and consequent hospitalization. Thirdly, this approach, which is at variance with current World Health Organization policy and guidelines, is cost-effective and readily implementable within the clinical setting. Finally, addressing the operational challenges to HIV-TB treatment integration can improve patient outcomes with substantial public health by reducing mortality by the most important causes of death in South Africa.
Evaluation of a measles immunisation campaign in Natal/KwaZulu.
(1990) Abdool Karim, Salim Safurdeen.
Routinely collected data on vaccines supplied and administered, measles notifications and hospital admissions for measles were used to evaluate the 1990 measles immunisation campaign in Natal/KwaZulu. comparisons of the monthly averages during the 12 month period before the campaign, 4 months of the campaign and 12 months after the campaign indicated that the 1990 measles campaign in Natal/KwaZulu demonstrated that the campaign was limited, not by design, to blacks only. The campaign galvanised a high degree of participation from almost all health services in this region and resulted in a rapid and marked plunge in the incidence of measles as reflected by declines in both measles notifications and measles hospital admissions. There was no deleterious shortterm residual effect of the measles campaign on routine measles immunisation services. The spillover effects of the measles campaign on routine immunisation services against polio, tuberculosis and tetanus was generally beneficial. While the campaign was a success in generating involvement of health services in Natal/KwaZulu and reducing the burden of measles in this region, this disease has not been eliminated. Vigilance and continued routine vaccination efforts are required to prevent further epidemics of measles in Natal/KwaZulu.
Incidence of HIV infection in rural KwaZulu-Natal in the context of the epidemiology and impact of HIV/AIDS in South Africa.
(2007) Gouws, Eleanor.; Abdool Karim, Salim Safurdeen.; Jinabhai, Champaklal Chhaganlal.
South Africa has had one of the fastest growing HIV epidemics in the world and almost 30% of women attending public antenatal clinics (ANC) are currently infected with the virus. But as the epidemic is starting to level off and antiretroviral therapy (ART) is becoming increasingly available, few methods exist to determine the impact of ART or other interventions on the epidemic in South Africa. This thesis explores the epidemiology and dynamics of HIV infection and investigates the potential impact of ART. Methods Total and age-specific prevalence data are analysed in time and space and are used to investigate patterns of infection in men and women, urban and rural, and low and high risk populations. Dynamical models are developed to estimate incidence from age-specific prevalence and trends over time and are compared to laboratory-based estimates of recent HIV sero-conversion. Incidence is estimated in different populations in South Africa. A dynamical model is developed to estimate the impact of ART on the future course of the HIV epidemic. Results HIV prevalence varies geographically and by age, sex and race. The average female-tomale HIV prevalence ratio is 1.7 and prevalence peaks at an older age among men than women. The age at which prevalence peaks among women has increased from 23.0 to 26.5 years between 1995 and 2002. Four patterns of infection are identified: among pregnant women attending ANCs, among men and women in the general population, and among migrant workers. HIV incidence among ANC attendees peaked in the mid to late 1990s (at 6.6% per year nationally) with variation between provinces. Current estimates of HIV prevalence and incidence among the general population in South Africa (aged 15-49 year) are 18.8% and 2.4% per year, respectively. Age-specific incidence estimates from dynamical models and laboratory methods are in good agreement provided the window period for the laboratory method is increased. Over the next ten years the provision of ART could avert 1 to 1.5 million deaths depending on whether it is provided when the CD4 cell count falls to 200 or 350 cells/ul. By 2015 about 1.1 million people will be receiving ART but this will have little impact on the incidence of HIV and scaling up of prevention efforts remains urgent. Conclusions The thesis explores some of the determinants and patterns of HIV prevalence and incidence in South Africa in order to find better ways to manage the epidemic of HIV, monitor changes and evaluate progress in control efforts. In order to fight the epidemic we need to mobilize the best possible science in support of those people and communities affected by the epidemic.
Pharmacokinetic and pharmacodynamic characteristics of isoniazid and rifampicin in patients with multidrug-resistant tuberculosis.
Pillai, Goonaseelan.; Miller, Raymond Martin.; Abdool Karim, Salim Safurdeen.
No abstract available.
Predictors of HIV acquisition in high risk women in Durban, South Africa.
(2015) Naicker, Nivashnee.; Kharsany, Ayesha Bibi Mahomed.; Abdool Karim, Salim Safurdeen.
In South Africa young women bear a disproportionate burden of HIV infection however, risk factors for HIV acquisition are not fully understood in this setting. In a cohort of 245 HIV negative women, we used proportional hazard regression analysis to examine the association of demographic, clinical and behavioural characteristics with HIV acquisition. The overall HIV incidence rate (IR) was 7.20 per 100 women years (wy), 95% Confidence Interval (CI) 4.20–9.80]. Women 18 to 24 years had the highest HIV incidence [IR 13.20 per 100 wy, 95% CI 6.59–23.62] and were almost three times more likely to acquire HIV compared to women 25 years and older [adjusted Hazard Ratio (aHR) 2.61, 95% CI 1.05–6.47]. Similarly, women in relationships with multiple sex partners [IR 8.97 per 100 wy, 95% CI 5.40–14.0] had more than twice the risk of acquiring HIV when compared to women who had no partner or who had a husband or stable partner (aHR 2.47, 95% CI 0.98–6.26). HIV prevention programmes must address young women’s vulnerability and promote safer sex practices for high risk women.
The role of natural killer cells in preventing HIV-1 acquisition and controlling disease progression.
(2013) Naranbhai, Vivek.; Abdool Karim, Salim Safurdeen.; Carr, William Henry.
In sub-Saharan Africa, women carry a disproportionate burden of the Human Immunodeficiency Virus Type 1 (HIV-1) pandemic. The high risk of HIV acquisition in these women and the variability in their disease progression is not fully understood. Natural Killer (NK) cells, which are innate immune antiviral lymphocytes, present systemically and at mucosal surfaces, may play a role in preventing HIV acquisition and/or altering disease progression, as they are key early mediators of the response to viral infections and are equipped to kill infected cells. The purpose of this study was to evaluate the role of NK cells in HIV-1 acquisition and following acquisition, in disease progression. The study participants were selected women who were participating in a randomized controlled trial assessing the effectiveness of 1% Tenofovir gel in preventing HIV-1 (CAPRISA 004 trial). The study design was a case-control study nested within the cohorts followed up in the CAPRISA 004 trial. In this trial, 889 sexually-active women aged 18-40 years were randomized to receive Tenofovir or placebo gel and prospectively followed. Assessment of HIV infection was performed monthly by rapid HIV-1 antibody tests, supplemented by HIV-1 RNA polymerase chain reaction (PCR), p24 Western blotting and/or ELISA. Samples obtained prior to the first positive rapid antibody test were retrospectively tested by HIV specific PCR to identify window period infections. The date of infection in this study was estimated as the midpoint between the last negative and first positive antibody test, or 14 days prior to the first HIV-1 RNA-PCR positive result. Multi-parametric flow cytometry techniques developed and validated in healthy blood donors were used to asses the bidirectional relationship between NK cells and HIV-1. To simulate in vivo interaction between NK cells and autologous HIV infected cells, an in vitro infection and coculture assay was used in addition to conventional assays of NK cell recognition of HLA-deficient cell lines. These were supplemented with measurement of plasma cytokines by Luminex and microbial products by ELISA. In this study, 44 cases who acquired HIV-1 were sampled prior to infection and 39 controls who remained HIV-1 negative despite high behavioural exposure at the timepoint when their preceding sexual activity was highest. To understand how HIV infection affected NK cells during early HIV-1 infection, the first sample obtained after acquisition was studied and compared to preinfection samples from the same participant. The case and control groups were broadly similar in the proportions using tenofovir gel, proportions infected with HSV-2 and number of sexual partners but tended to be marginally older than cases (27.6 vs 23.3 years). By design control women had higher sexual activity than cases (mean 11 vs. 5.7 sex acts per month). The frequency of IFN-γ secreting NK cells from women who acquired HIV infection were significantly lower than from women who remained uninfected in response to 721 cells-an EBV transformed B cell line (background-adjusted median 13.7% vs. 21.6%; p=0.03) and to autologous HIV infected T-cells (background-adjusted median 0.53% vs. 2.09%; p=0.007). NK cells from HIV acquirers displayed impaired proliferation but enhanced spontaneous degranulation compared with non-acquirers after co-culture with HIV uninfected or infected autologous T-cell blasts. Adjusting for age, gel arm, HSV-2 infection status and levels of NK cell activation, IFN-γ+ NK cell responses to autologous HIV infected cells were associated with reduced odds of HIV acquisition (OR 0.582; 95% CI 0.35-0.98; p=0.04). In addition, even in the absence of ex vivo stimulation, HIV acquirers had higher levels of generalised innate immune activation measured by systemic cytokine concentrations (TNF-α, IL2, IL-7 and IL12p40), peripheral blood platelet concentrations (p=0.038), and non-specific ex vivo NK cell activation (p<0.001). Generalised NK cell activation measured directly ex vivo without stimulation was associated with acquisition. Further, if innate immune activation was assembled as a principal component in an unsupervised fashion but taking into account all the measures made, it was significantly associated with HIV acquisition (OR adjusted for age, tenofovir gel use, and HSV-2 status for PC with innate immune factor loadings 11.27; 95% CI 1.84- 69.09; p=0.009). The causes of preinfection innate immune activation could not be established in this study but the degree of activation could not be explained by microbial translocation as both HIV acquirers and non-acquirers had similar levels of plasma lipopolysaccharide (LPS), soluble CD14 (sCD14) and intestinal fatty-acid binding protein (I-FABP). Similarly, both HIV acquirers and non-acquirers had similar NK cell and cytokine responses to Toll-like Receptor (TLR)-2, 3 or 7/8 agonists 11. During early HIV-infection, NK cells demonstrated significantly higher activation (p=0.03), expression of Killer-cell immunoglobulin-like Receptors (KIR) (p=0.006) and expression of chemokine receptor 7 (CCR7, p<0.0001) compared with prior to acquisition. Although NK cells had reduced cytolytic potential following HIV acquisition, antiviral IFN-γ secretion appeared to be preserved. NK cell responses were not different between tenofovir and placebo gel recipients, but women who acquired HIV whilst using tenofovir gel had higher gag-specific IFN-γ CD4+ T-cell responses during early infection. Overall, the findings suggest that the frequency of NK cells producing IFN-γ specifically after co-culture with HIV-1 infected target cells was associated with protection from HIV-1 acquisition but, generalised, non-specific activation of NK cells and other innate immune components enhanced HIV acquisition. Since neither microbial translocation nor TLR responsiveness were associated with pre-existing immune activation further studies will be required to identify the drivers of generalised innate immune activation. Methods to dampen generalised innate immune activation and/or augment specific NK cell antiviral responses in women at risk for HIV-1 may reduce HIV-1 acquisition. During primary HIV-1 infection, NK cells underwent impairment of cytolytic function but not IFN-γ secretory function; this may affect their ability to affect disease progression. Although Tenofovir gel did not alter innate immune responses in women with breakthrough infection, it preserved HIV-specific Tcell immune responses, the consequences of which need further exploration. Understanding how Tenofovir gel mediated preservation of adaptive immune responses may lead to interventions that will reinforce protective host responses. In conclusion, innate immune responses by NK cells have been shown to impact HIV acquisition; HIV-specific IFN-γ responses by NK cells were protective while generalised NK activation was detrimental. The causes of innate immune activation are not known but these effects were independent of the impact of Tenofovir gel. Future prevention strategies targeting mucosal transmission of HIV should assess their impact on NK cell responses, to avoid general innate immune activation and enhance their ability to protect against HIV acquisition.
Skin disorders in primary health care in KwaZulu-Natal : testing for solutions after assessment of burden of disease, and evaluation of resources.
(2007) Aboobaker, Jamila B.; Abdool Karim, Salim Safurdeen.; Taylor, Myra.; Coovadia, Hoosen Mahomed.
No abstract available.

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