Adolescent HIV treatment issues in South Africa.

CAPRISA, 2015.Abstract available in pdf

Inaccuracy of Death Certificate Diagnosis of Tuberculosis and Potential Underdiagnosis of TB in a Region of High HIV Prevalence

Despite the South African antiretroviral therapy rollout, which should reduce the incidence of HIV-associated tuberculosis (TB), the number of TB-attributable deaths in KwaZuluNatal (KZN) remains high. TB is often diagnosed clinically, without microbiologic confirmation, leading to inaccurate estimates of TB-attributed deaths. This may contribute to avoidable deaths, and impact population-based TB mortality estimates. Objectives. (1) To measure the number of cases with microbiologically confirmed TB in a retrospective cohort of deceased inpatients with TB-attributed hospital deaths. (2) To estimate the rates of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB in this cohort. Results. Of 2752 deaths at EDH between September 2006 and March 2007, 403 (15%) were attributed to TB on the death certificate. 176 of the TB-attributed deaths (44%) had a specimen sent for smear or culture; only 64 (36%) had a TB diagnosis confirmed by either test. Of the 39 culture-confirmed cases, 27/39 (69%) had fully susceptible TB and 27/39 (69%) had smear-negative culture-positive TB (SNTB). Two patients had drug monoresistance, three patients had MDR-TB, and one had XDR-TB. Conclusions. Most TB-attributed deaths in this cohort were not microbiologically confirmed. Of confirmed cases, most were smear-negative, culture positive and were susceptible to all first line drugs

Eligibility for co-trimoxazole prophylaxis among adult HIV-infected patients in South Africa

Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) is a broad-spectrum antibiotic used to prevent opportunistic infections in patients with HIV infection. Primary prophylaxis with co-trimoxazole has been shown to decrease hospitalisation, morbidity and mortality among people living with HIV, primarily by decreasing rates of malaria, pneumonia, diarrhoea, Pneumocystis pneumonia, toxoplasmosis and severe bacterial infections.[1-4] Co-trimoxazole is inexpensive and widely available. In standard adult treatment guidelines and essential medicine lists in South Africa (SA), the current recommendation is that co-trimoxazole should be provided for HIV-infected patients with a CD4+ count ˂200 cells/μL, HIV/tuberculosis (TB) co-infection and/or advanced HIV disease (World Health Organization (WHO) stage 3 or 4). Because of expanded access and progression towards initiation of antiretroviral treatment (ART), the WHO issued updated guidelines for co-trimoxazole prophylaxis in 2014.[5] These guidelines recommend co-trimoxazole prophylaxis for adults (including pregnant women) with severe or advanced HIV clinical disease (WHO stage 3 or 4) and/or with a CD4+ count ≤350 cells/μL. In settings with a high prevalence of malaria and/or severe bacterial infections, prophylaxis is recommended for all patients regardless of WHO clinical stage or CD4+ cell count. However, the timing of discontinuation of co-trimoxazole prophylaxis may vary and is dependent on the malarial/ bacterial infection burden in different settings.[5] Therefore, the current WHO guidance should be adapted in the context of a country-specific epidemiological profile and priorities. The impact and benefit of co-trimoxazole prophylaxis on morbidity and mortality among HIV-infected patients with a CD4+ count ≤350 cells/μL in regions with high infectious disease burdens (irrespective of CD4+ count) have been shown in a good-quality systematic review and meta-analysis that included both randomised controlled trials (RCTs) and observational cohort studies.[6] This extensive systematic review by Suthar et al.[6] showed that co-trimoxazole prophylaxis reduced the rate of death when initiated at CD4+ counts ≤350 cells/μL with ART in populations in Africa and Asia. Co-trimoxazole prophylaxis in ART-naive patients with CD4+ counts >350 cells/μL reduced the rate of death and malaria, and continuation of prophylaxis after ART-induced recovery with CD4+ counts >350 cells/μL reduced hospital admission, pneumonia, malaria and diarrhoea in African populations (SA, Zimbabwe, Uganda, Malawi, Mozambique and Ethiopia).[6] While this review largely informed the 2014 WHO guideline update, the findings need to be interpreted in the context of studies included and the varied epidemiological profile across middle- and low-income countries. There were only 2 relatively small RCTs with very few events of key endpoints; therefore, the finding of non-significance was likely (e.g. total of ~5 deaths in both arms from both trials).[7,8] One of the 2 studies was unblinded, and the follow-up in the other study was only 4 months. Ongoing co-trimoxazole prophylaxis was better than discontinuation of the drug at CD4+ counts >200 cells/μL for 3 endpoints with an adequate number of events (pneumonia, diarrhoea and malaria). Furthermore, 8 of 9 studies were conducted in countries with a high burden of malaria and bacterial and parasitic diseases, which is generalisable to the SA context.[9] Although seasonal malaria occurs in the north-eastern parts of SA, the incidence of malaria mortality and morbidity has declined remarkably over time (˂10 000 cases annually for the past 10 years).[10] In contrast, in Uganda, >9 million confirmed cases of malaria were reported in the public health sector in 2015.[9] In this review, further stratification of the impact of co-trimoxazole prophylaxis at CD4+ counts ˂200 cells/μL v. 200 - 350 cells/μL was not available. Lower bacterial resistance to co-trimoxazole is possible among populations included in this review, while resistance to co-trimoxazole in SA is common in patients with community-acquired bacterial infections.[11-13] This potential risk of resistance compounded by the lack of long-term toxicity data needs to be weighed against recommending prophylaxis in populations where benefit has not been established. Local observational studies suggest no benefit of co-trimoxazole prophylaxis with a CD4+ count >200 cells/μL or in patients who were not WHO clinical stage 3 or 4.[14,15] In an observational cohort of patients attending the adult HIV clinics at the University of Cape Town, SA, the effect of prophylactic low-dose co-trimoxazole on survival and morbidity was examined over a 5-year follow-up period. Co-trimoxazole reduced the hazards of mortality by ~44% and the incidence of severe HIV-related illnesses by ~48% in patients with evidence of advanced immunosuppression (WHO stage 3 or 4) or laboratory measurement of total lymphocyte count ˂1 250 × 106/L or CD4+ count ˂200 cells/μL. However, no beneficial effect was seen in patients with WHO clinical stage 2 or CD4+ count 200 - 500 cells/μL. A potential limitation of this study was that the sample size of patients with a CD4+ count 200 - 500 cells/μL receiving co-trimoxazole was small and may have been underpowered to observe a significant benefit. In this study, patients on ART were excluded.[14] In another SA cohort study by Hoffmann et al.,[15] examining co-trimoxazole effectiveness in reducing mortality risk during ART among persons with a CD4+ count >200 cells/μL and varying WHO clinical stages, overall co-trimoxazole prophylaxis reduced mortality by 36% across all CD4+ count strata. Analysis stratified by baseline CD4+ count showed a similar reduction in mortality risk among persons with a CD4+ count ˂200 cells/μL, but no statistically significant association was found between co-trimoxazole prophylaxis and survival in the subgroup of persons with a CD4+ count >200 - 350 cells/μL, CD4+ count >350 cells/μL and WHO stage 1 or 2 disease. However, the findings of this study need to be interpreted cautiously for the following reasons: the group with a CD4+ count >350 cells/μL was small (n=917) and might not have had enough events to draw inferences; the study population was a cohort of miners and might not have been potentially representative of the SA population; and, being a non-randomised study, residual confounding might have been a potential limitation. An earlier Cochrane review established the benefit of initiating prophylaxis at a CD4+ count ˂200 cells/μL in those with stage 2, 3 or 4 HIV disease (including TB), and discontinuation once the CD4+ count was >200 cells/μL for >6 months.[16] There was a reduction of ~31% in mortality, 27% in morbid events and 55% in hospitalisation. Significant reductions were also detected for bacterial and parasitic infections and for Pneumocystis jirovecii pneumonia. Considering the above-mentioned evidence gaps and lack of generalisability of studies to SA, the current National Essential Medicines List Committee and Adult Hospital-Level Technical Sub-committee do not support the implementation of the updated guidance by the WHO for co-trimoxazole prophylaxis among adult HIV-infected patients. Efforts should be directed towards exploring several research gaps. The impact of co-trimoxazole prophylaxis on morbidity and mortality at higher CD4+ counts in low-malariaburden areas needs to be investigated further. More data are needed on timing of co-trimoxazole cessation in HIV and TB co-infection in our context

Eligibility for co-trimoxazole prophylaxis among adult HIV-infected patients in South Africa

Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) is a broad-spectrum antibiotic used to prevent opportunistic infections in patients with HIV infection. Primary prophylaxis with co-trimoxazole has been shown to decrease hospitalisation, morbidity and mortality among people living with HIV, primarily by decreasing rates of malaria, pneumonia, diarrhoea, Pneumocystis pneumonia, toxoplasmosis and severe bacterial infections.[1-4] Co-trimoxazole is inexpensive and widely available. In standard adult treatment guidelines and essential medicine lists in South Africa (SA), the current recommendation is that co-trimoxazole should be provided for HIV-infected patients with a CD4+ count ˂200 cells/μL, HIV/tuberculosis (TB) co-infection and/or advanced HIV disease (World Health Organization (WHO) stage 3 or 4). Because of expanded access and progression towards initiation of antiretroviral treatment (ART), the WHO issued updated guidelines for co-trimoxazole prophylaxis in 2014.[5] These guidelines recommend co-trimoxazole prophylaxis for adults (including pregnant women) with severe or advanced HIV clinical disease (WHO stage 3 or 4) and/or with a CD4+ count ≤350 cells/μL. In settings with a high prevalence of malaria and/or severe bacterial infections, prophylaxis is recommended for all patients regardless of WHO clinical stage or CD4+ cell count. However, the timing of discontinuation of co-trimoxazole prophylaxis may vary and is dependent on the malarial/ bacterial infection burden in different settings.[5] Therefore, the current WHO guidance should be adapted in the context of a country-specific epidemiological profile and priorities. The impact and benefit of co-trimoxazole prophylaxis on morbidity and mortality among HIV-infected patients with a CD4+ count ≤350 cells/μL in regions with high infectious disease burdens (irrespective of CD4+ count) have been shown in a good-quality systematic review and meta-analysis that included both randomised controlled trials (RCTs) and observational cohort studies.[6] This extensive systematic review by Suthar et al.[6] showed that co-trimoxazole prophylaxis reduced the rate of death when initiated at CD4+ counts ≤350 cells/μL with ART in populations in Africa and Asia. Co-trimoxazole prophylaxis in ART-naive patients with CD4+ counts >350 cells/μL reduced the rate of death and malaria, and continuation of prophylaxis after ART-induced recovery with CD4+ counts >350 cells/μL reduced hospital admission, pneumonia, malaria and diarrhoea in African populations (SA, Zimbabwe, Uganda, Malawi, Mozambique and Ethiopia).[6] While this review largely informed the 2014 WHO guideline update, the findings need to be interpreted in the context of studies included and the varied epidemiological profile across middle- and low-income countries. There were only 2 relatively small RCTs with very few events of key endpoints; therefore, the finding of non-significance was likely (e.g. total of ~5 deaths in both arms from both trials).[7,8] One of the 2 studies was unblinded, and the follow-up in the other study was only 4 months. Ongoing co-trimoxazole prophylaxis was better than discontinuation of the drug at CD4+ counts >200 cells/μL for 3 endpoints with an adequate number of events (pneumonia, diarrhoea and malaria). Furthermore, 8 of 9 studies were conducted in countries with a high burden of malaria and bacterial and parasitic diseases, which is generalisable to the SA context.[9] Although seasonal malaria occurs in the north-eastern parts of SA, the incidence of malaria mortality and morbidity has declined remarkably over time (˂10 000 cases annually for the past 10 years).[10] In contrast, in Uganda, >9 million confirmed cases of malaria were reported in the public health sector in 2015.[9] In this review, further stratification of the impact of co-trimoxazole prophylaxis at CD4+ counts ˂200 cells/μL v. 200 - 350 cells/μL was not available. Lower bacterial resistance to co-trimoxazole is possible among populations included in this review, while resistance to co-trimoxazole in SA is common in patients with community-acquired bacterial infections.[11-13] This potential risk of resistance compounded by the lack of long-term toxicity data needs to be weighed against recommending prophylaxis in populations where benefit has not been established. Local observational studies suggest no benefit of co-trimoxazole prophylaxis with a CD4+ count >200 cells/μL or in patients who were not WHO clinical stage 3 or 4.[14,15] In an observational cohort of patients attending the adult HIV clinics at the University of Cape Town, SA, the effect of prophylactic low-dose co-trimoxazole on survival and morbidity was examined over a 5-year follow-up period. Co-trimoxazole reduced the hazards of mortality by ~44% and the incidence of severe HIV-related illnesses by ~48% in patients with evidence of advanced immunosuppression (WHO stage 3 or 4) or laboratory measurement of total lymphocyte count ˂1 250 × 106/L or CD4+ count ˂200 cells/μL. However, no beneficial effect was seen in patients with WHO clinical stage 2 or CD4+ count 200 - 500 cells/μL. A potential limitation of this study was that the sample size of patients with a CD4+ count 200 - 500 cells/μL receiving co-trimoxazole was small and may have been underpowered to observe a significant benefit. In this study, patients on ART were excluded.[14] In another SA cohort study by Hoffmann et al.,[15] examining co-trimoxazole effectiveness in reducing mortality risk during ART among persons with a CD4+ count >200 cells/μL and varying WHO clinical stages, overall co-trimoxazole prophylaxis reduced mortality by 36% across all CD4+ count strata. Analysis stratified by baseline CD4+ count showed a similar reduction in mortality risk among persons with a CD4+ count ˂200 cells/μL, but no statistically significant association was found between co-trimoxazole prophylaxis and survival in the subgroup of persons with a CD4+ count >200 - 350 cells/μL, CD4+ count >350 cells/μL and WHO stage 1 or 2 disease. However, the findings of this study need to be interpreted cautiously for the following reasons: the group with a CD4+ count >350 cells/μL was small (n=917) and might not have had enough events to draw inferences; the study population was a cohort of miners and might not have been potentially representative of the SA population; and, being a non-randomised study, residual confounding might have been a potential limitation. An earlier Cochrane review established the benefit of initiating prophylaxis at a CD4+ count ˂200 cells/μL in those with stage 2, 3 or 4 HIV disease (including TB), and discontinuation once the CD4+ count was >200 cells/μL for >6 months.[16] There was a reduction of ~31% in mortality, 27% in morbid events and 55% in hospitalisation. Significant reductions were also detected for bacterial and parasitic infections and for Pneumocystis jirovecii pneumonia. Considering the above-mentioned evidence gaps and lack of generalisability of studies to SA, the current National Essential Medicines List Committee and Adult Hospital-Level Technical Sub-committee do not support the implementation of the updated guidance by the WHO for co-trimoxazole prophylaxis among adult HIV-infected patients. Efforts should be directed towards exploring several research gaps. The impact of co-trimoxazole prophylaxis on morbidity and mortality at higher CD4+ counts in low-malariaburden areas needs to be investigated further. More data are needed on timing of co-trimoxazole cessation in HIV and TB co-infection in our context

Association of -308 TNF-alpha promoter polymorphism with viral load and CD4 T-helper cell apoptosis in HIV-1 infected black South Africans

Objective. To determine whether the -308 TNF-α promoter polymorphism is associated with markers of HIV progression in the South African population. Methods. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the -308 TNF-α polymorphism in 75 patients and 76 healthy controls. Serum TNF-α concentrations were measured using ELISA in each cohort. CD4+ T cell apoptosis and HIV-1 RNA viral load were determined using Annexin-V-FITC assay and Nuclisens Easy Q HIV-1 assay respectively. CD4 + T cell counts were measured flow cytometrically. Results. The frequency of -308 G allele was similar in the HIV-1 and control cohorts. The -308GG genotype was associated with lower TNF-α concentrations and markers of increased HIV progression indicated by higher TH lymphocyte apoptosis, lower TH lymphocyte count and higher plasma viral load, irrespective of treatment. Conclusion. The presence of the TNF-α -308 G allele in HIV-1 patients may be associated with increased risk of HIV-1 progression. Further research is required to investigate the nature of this association. S Afr J HIV Med 2012;13(2):72-77

A review of progress on HIV, AIDS and Tuberculosis.

As a United Nations member state, South Africa is signatory to the Millennium Declaration and is committed to achieve the Millennium Development Goals (MDGs) and targets for 2015. This chapter provides an overview of the status of South Africa’s response to MDG 6 with a specific focus on the progress made to date with respect to HIV and tuberculosis (TB) – two intertwined epidemics contributing disproportionately to morbidity and premature mortality in South Africa. These epidemics are also closely linked to MDG 4 and 5 outcomes. Any progress made by South Africa to reverse current trends will have substantial implications for the global MDG targets as well as country level outcomes. This chapter will use available evidence to document the status of HIV and TB in South Africa relative to the South African Ministry of Health’s strategy to address these diseases

Importance of early identification of PrEP breakthrough infections in a generalized HIV epidemic: a case report from a PrEP demonstration project in South Africa

Background The World Health Organisation recommends the use of tenofovir-containing pre-exposure prophylaxis (PrEP) as an additional Human Immunodeficiency Virus (HIV) prevention choice for men and women at substantial risk of HIV infection. PrEP could fill an important HIV prevention gap, especially for sexually active young women who are limited in their ability to negotiate mutual monogamy or condom use. As PrEP is scaled up in high HIV incidence settings, it is crucial to consider the importance of early identification of HIV infection during PrEP use, to allow for rapid discontinuation of PrEP to reduce the risk of antiretroviral (ARV) resistance. The purpose of this case study is to provide this critical evidence. Case presentation This report describes a 20-year-old woman in a HIV sero-discordant relationship who initiated oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)) through a demonstration project (CAPRISA 084) in October 2017. Despite good adherence throughout her PrEP use, she tested HIV antibody positive at month nine of study participation. Retrospective testing showed increasing HIV viral load over time, and retrospective use of fourth-generation rapid HIV tests showed HIV detection (positive antigen/antibody) at month one. Sequencing confirmed a dominant wild type at month one with dual therapy resistance patterns emerging by month three (M184V and K65R mutations), which is suggestive of protracted PrEP use during an undetected HIV infection. The participant was referred to infectious diseases for further management of her HIV infection and was initiated on a first line, tenofovir-sparing regimen. At the time of this report (January 2020), the participant had been on ARV- therapy (ART) for 13 months and had no signs of either clinical, immunologic or virologic failure. Conclusions This case report highlights the importance of appropriate HIV screening during wider oral PrEP scale-up in high HIV incidence settings to circumvent the consequences of prolonged dual therapy in an undiagnosed HIV infection and in turn prevent ARV resistance