Articles tagged as "Zambia"

Xpert testing - rationalise with chest X-ray or HIV pre-screening?

Implementation research to inform the use of Xpert MTB/RIF in primary health care facilities in high TB and HIV settings in resource constrained settings.

Muyoyeta M, Moyo M, Kasese N, Ndhlovu M, Milimo D, Mwanza W, Kapata N, Schaap A, Godfrey Faussett P, Ayles H. PLoS One. 2015 Jun 1;10(6):e0126376. doi: 10.1371/journal.pone.0126376. eCollection 2015.

Background: The current cost of Xpert MTB RIF (Xpert) consumables is such that algorithms are needed to select which patients to prioritise for testing with Xpert.

Objective: To evaluate two algorithms for prioritisation of Xpert in primary health care settings in a high TB and HIV burden setting.

Method: Consecutive, presumptive TB patients with a cough of any duration were offered either Xpert or Fluorescence microscopy (FM) test depending on their CXR score or HIV status. In one facility, sputa from patients with an abnormal CXR were tested with Xpert and those with a normal CXR were tested with FM ("CXR algorithm"). CXR was scored automatically using a Computer Aided Diagnosis (CAD) program. In the other facility, patients who were HIV positive were tested using Xpert and those who were HIV negative were tested with FM ("HIV algorithm").

Results: Of 9482 individuals pre-screened with CXR, Xpert detected TB in 2090/6568 (31.8%) with an abnormal CXR, and FM was AFB positive in 8/2455 (0.3%) with a normal CXR. Of 4444 pre-screened with HIV, Xpert detected TB in 508/2265 (22.4%) HIV positive and FM was AFB positive in 212/1920 (11.0%) in HIV negative individuals. The notification rate of new bacteriologically confirmed TB increased; from 366 to 620/100 000/yr and from 145 to 261/100 000/yr at the CXR and HIV algorithm sites respectively. The median time to starting TB treatment at the CXR site compared to the HIV algorithm site was: 1(IQR 1-3 days) and 3 (2-5 days) (p<0.0001) respectively.

Conclusion: Use of Xpert in a resource-limited setting at primary care level in conjunction with pre-screening tests reduced the number of Xpert tests performed. The routine use of Xpert resulted in additional cases of confirmed TB patients starting treatment. However, there was no increase in absolute numbers of patients starting TB treatment. Same day diagnosis and treatment commencement was achieved for both bacteriologically confirmed and empirically diagnosed patients where Xpert was used in conjunction with CXR.

Abstract  Full-text [free] access

Editor’s notes: Although many countries have begun to deploy molecular TB diagnostics, the cost of these technologies remains prohibitive for widespread use in low- and middle-income countries. This study in Zambian primary health care clinics aimed to explore whether the use of Xpert® MTB/RIF could be rationalised by pre-screening individuals with cough, either by chest X-ray (CXR) or by HIV testing. CXR screening only marginally reduced the use of Xpert® (as three-quarters of people screened had an abnormal CXR, using digital X-ray and computerised interpretation). Restricting use of Xpert® to those known to be HIV-positive reduced the number of Xpert® tests by around half. Under both algorithms, the proportion testing Xpert® positive was very high (22-32%), suggesting that too few people were being identified as needing TB investigation. Similar to other studies of Xpert® implementation, the overall number of people starting TB treatment did not increase with the introduction of Xpert®. However, the proportion of people starting TB treatment who had microbiological confirmation did increase substantially under both algorithms. Empirical TB treatment (meaning initiation of treatment without microbiological confirmation) remained common, in the X-ray algorithm particularly where a third of people with an abnormal CXR but a negative Xpert® were started on TB treatment. This study was not designed to determine how many people who genuinely had TB were missed by each algorithm. Also this paper did not include cost-effectiveness analyses. Based on this evidence, neither of these algorithms can be clearly recommended. Further evaluation of different screening and testing strategies will be important to inform the scale-up of molecular diagnostics.   

Avoid TB deaths
Africa
Zambia
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People living with HIV at higher risk of developing disabilities in sub-Saharan Africa

The relationship between HIV and prevalence of disabilities in sub-Saharan Africa: systematic review.

Banks LM, Zuurmond M, Ferrand R, Kuper H. Trop Med Int Health. 2015 Apr;20(4):411-29. doi: 10.1111/tmi.12449. Epub 2015 Jan 14.

Objective: To systematically review evidence on the prevalence and risk of disabilities among children and adults living with HIV in sub-Saharan Africa.

Methods: Articles were identified from 1980 to June 2013 through searching seven electronic databases. Epidemiological studies conducted in sub-Saharan Africa that explored the association between HIV status and general disability or specific impairments, with or without an HIV-uninfected comparison group, were eligible for inclusion.

Results: Of 12 867 records initially identified, 61 papers were deemed eligible for inclusion. The prevalence of disability was high across age groups, impairment types and study locations. Furthermore, 73% of studies using an HIV- comparator found significantly lower levels of functioning in people living with HIV (PLHIV). By disability type, the results were as follows: (i) for studies measuring physical impairments (n = 14), median prevalence of limitations in mobility and motor function among PLHIV was 25.0% (95% CI: 21.8-28.2%). Five of eight comparator studies found significantly reduced functioning among PLHIV; for arthritis, two of three studies which used an HIV- comparison group found significantly increased prevalence among PLHIV; (ii) for sensory impairment studies (n = 17), median prevalence of visual impairment was 11.2% (95%CI: 9.5-13.1%) and hearing impairment was 24.1% (95%CI: 19.2-29.0%) in PLHIV. Significantly increased prevalence among PLHIV was found in one of four (vision) and three of three studies (hearing) with comparators; (iii) for cognitive impairment in adults (n = 30), median prevalence for dementia was 25.3% (95% CI: 22.0-28.6%) and 40.9% (95% CI: 37.7-44.1%) for general cognitive impairment. Across all types of cognitive impairment, twelve of fourteen studies found a significant detrimental effect of HIV infection; (iv) for developmental delay in children with HIV (n = 20), median prevalence of motor delay was 67.7% (95% CI: 62.2-73.2%). All nine studies that included a comparator found a significant difference between PLHIV and controls; for cognitive development and global delay, a significant detrimental effect of HIV was found in five of six and one of two studies, respectively. In the nine cohort studies comparing vertically infected and uninfected children, eight showed a significant gap in development over time in children with HIV. Finally, fifteen of thirty-one (48%) studies found a statistically significant dose-response relationship between indicators of disease progression (CD4 or WHO stage) and disability.

Conclusions: HIV is widespread in sub-Saharan Africa and the evidence suggests that it is linked to disabilities, affecting a range of body structures and functions. More research is needed to better understand the implications of HIV-related disability for individuals, their families as well as those working in the fields of disability and HIV so that appropriate interventions can be developed.

Abstract  Full-text [free] access

Editor’s notes: As ART is scaled-up, and people living with HIV live longer, an increasing number of people will face challenges of HIV-associated disability. Disability may be partly a direct effect of living with HIV, but may also be an indirect effect, for example due to side effects of treatment. There has been relatively little research on this topic, particularly in low and middle-income countries and this is the first systematic review of the prevalence of disability among people living with HIV in sub-Saharan Africa. The review found a high prevalence of all categories of disability. The majority of studies had an HIV-negative comparison group among whom levels of disability were lower than among people living with HIV. Developmental delay was the impairment most strongly linked to HIV, with prevalence as high as 78% in children living with HIV. To minimize the chance that the observed association was due to reverse causality, the review excluded studies which clearly focused on disability as a risk factor for HIV, although it is likely that some studies still included individuals in whom disability preceded HIV infection. There was also relatively little data on ART status and duration in many studies, which may impact on the association of HIV and disability.  Despite these limitations, this study highlights the need to focus on prevention and management of HIV-associated disability in sub-Saharan Africa and development of effective, low-cost evidence-informed activities.

Africa
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Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors from concluding that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools - rapid tests for hepatitis B surface antigen - are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

Avoid TB deaths
Africa
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Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors to conclude that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools such as rapid tests for hepatitis B surface antigen are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

Avoid TB deaths
Africa
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Cryptococcal antigen screening plus home visits reduces early mortality

Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial.

Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, Chijoka C, Masasi A, Kimaro G, Ngowi B, Kahwa A, Mwaba P, Harrison TS, Egwaga S, Jaffar S, REMSTART trial team. Lancet. 2015 Mar 9. pii: S0140-6736(15)60164-7. doi: 10.1016/S0140-6736(15)60164-7. [Epub ahead of print]

Background: Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening.

Methods: We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age ≥18 years, CD4 count of <200 cells per uL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6-8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413.

Findings: Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10-43) lower in the clinic plus community support group than in standard care group (p=0.004).

Interpretation: Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa.

Abstract access 

Editor’s notes: Despite the huge success of antiretroviral programme roll-out, early mortality among people initiating antiretroviral therapy (ART) in low- and middle-income countries remains high, and reducing early mortality is a priority. The risk of early mortality is highest among people with low CD4 counts. Although there has been an increase over calendar time in the median CD4 count at ART start, many people still start ART with low CD4 counts, and continue to be at high risk of death.

Cryptococcal disease is consistently identified at autopsy among HIV-positive people, although less commonly than tuberculosis and other lung infections. Cryptococcal disease is typically seen among individuals with very low CD4 counts, and has high case-fatality, for reasons including late presentation and suboptimal treatment and care. Among people with low CD4 counts, cryptococcal antigen can be detected in blood several weeks before cryptococcal disease becomes symptomatic. In 2011, the World Health Organization (WHO) issued rapid advice concerning prevention and treatment of cryptococcal meningitis in resource-constrained settings. This included a conditional recommendation (based on low-quality evidence) to screen individuals with CD4 counts below 100 cells per µl for cryptococcal antigen, followed by treatment either for cryptococcal meningitis, or with fluconazole for asymptomatic cryptococcal antigenaemia, as appropriate.

This trial is the first to provide evidence that this strategy can save lives. This was a pragmatic, individually randomised trial enrolling HIV-positive, ART-naïve people initially with CD4 counts below 100 cells per µl. Because of slow enrolment, inclusion criteria were later expanded to include people with CD4 counts below 200 cells per µl. The programme had two components. The first involved screening for cryptococcal antigen with a point-of-care test using a finger prick blood sample, followed by management in line with WHO guidelines. The second was adherence support, with trained lay workers visiting participants at or near their homes weekly for the first four weeks. The lay workers delivered ART, provided adherence support and monitored for adverse events.

The reduction of mortality from 18% to 13% in the intervention arm is clearly important, but also intriguing in terms of identifying the “active ingredient”. This may be difficult in a pragmatic trial of a programme with more than one component. For example, there was no cryptococcal antigen testing in control arm participants. Thus we cannot assess precisely the reduction in mortality attributable to this component of the programme. The authors estimate that cryptococcal antigen screening and treatment contributed about half of the observed effect. This component is also interesting because in practice, implementation of the cryptococcal antigen “screen and treat” pathway in the trial was not exactly as per WHO guidelines. WHO guidelines recommend lumbar puncture for people who screen positive for cryptococcal antigen and have symptoms suggesting meningitis. However, in this trial 76% of people testing cryptococcal antigen positive refused lumbar puncture, similar to experience elsewhere. Despite the programme, 32% of people in the intervention arm who were cryptococcal antigen positive died. This suggests that the fluconazole that most people received may have been inadequate, and that alternatives to lumbar puncture are necessary to identify people at highest risk who would benefit from full treatment for cryptococcal meningitis with amphotericin B. Quantifying the cryptococcal antigen titre in blood might serve this purpose, and needs further investigation.

In a previous trial in Uganda, home-based ART care (monthly delivery of ART by lay workers) was as effective as clinic-based care, in terms of virologic failure. However, other programmes similarly aiming to provide support for individuals starting ART have been less successful. For example a recently-presented trial of health “navigators” who used mobile phones and text messages to help people living with HIV link to ART and, where relevant, TB treatment, did not reduce mortality at nine months. Supporting adherence and retention is clearly critical to the long-term success of ART programmes. The challenge is defining how to do this most effectively and sustainably.

As part of this trial, in both arms ART was intended to be started within four to seven days of the first visit where possible, substantially faster than was previously routine. All participants were asked to provide sputum for testing for tuberculosis with Xpert MTB/RIF, regardless of reported symptoms. Some 16% of participants were already on tuberculosis treatment at enrolment. A further 11% were newly-diagnosed with tuberculosis at enrolment, roughly half based on sputum smear or clinical features and half based on the Xpert MTB/RIF result. This emphasises the importance of routine investigation for tuberculosis among people presenting to start ART. In the United Republic of Tanzania, people not on tuberculosis treatment were rescreened with Xpert MTB/RIF six weeks after enrolment. A further 5% were found to have tuberculosis, highlighting the inadequate sensitivity of Xpert MTB/RIF on sputum in this group of people.

Overall this trial provides encouragement that early on-ART mortality among people with low CD4 counts can be reduced. This is achieved with targeted treatment of cryptococcal disease and home-based early adherence support, in the context of universal screening for tuberculosis and rapid ART initiation. Ongoing studies are investigating whether empirical treatment for tuberculosis will reduce early mortality among similar patient populations. These results together will help define the optimum package of care to minimise mortality among individuals presenting with low CD4 cell counts. At the same time, HIV testing needs to be promoted so that people living with HIV can start ART before reaching the stage of advanced disease where mortality is such a risk.

Avoid TB deaths
Africa
United Republic of Tanzania, Zambia
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TB common at post-mortem among medical inpatients in Zambia

Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study.  

Bates M, Mudenda V, Shibemba A, Kaluwaji J, Tembo J, Kabwe M, Chimoga C, Chilukutu L, Chilufya M, Kapata N, Hoelscher M, Maeurer M, Mwaba P, Zumla A. Lancet Infect Dis. 2015 Mar 9. pii: S1473-3099(15)70058-7. doi: 10.1016/S1473-3099(15)70058-7. [Epub ahead of print]

Background: Patients with subclinical tuberculosis, smear-negative tuberculosis, extrapulmonary tuberculosis, multidrug-resistant tuberculosis, and asymptomatic tuberculosis are difficult to diagnose and may be missed at all points of health care. We did an autopsy study to ascertain the burden of tuberculosis at post mortem in medical inpatients at a tertiary care hospital in Lusaka, Zambia.

Methods: Between April 5, 2012, and May 22, 2013, we did whole-body autopsies on inpatients aged at least 16 years who died in the adult inpatient wards at University Teaching Hospital, Lusaka, Zambia. We did gross pathological and histopathological analysis and processed lung tissues from patients with tuberculosis through the GeneXpert MTB/RIF assay to identify patients with multidrug-resistant tuberculosis. The primary outcome measure was specific disease or diseases stratified by HIV status. Secondary outcomes were missed tuberculosis, multidrug-resistant tuberculosis, and comorbidities with tuberculosis. Data were analysed using Pearson chi2, the Mann-Whitney U test, and binary logistic regression.

Findings: The median age of the 125 included patients was 35 years (IQR 29-43), 80 (64%) were men, and 101 (81%) were HIV positive. 78 (62%) patients had tuberculosis, of whom 66 (85%) were infected with HIV. 35 (45%) of these 78 patients had extrapulmonary tuberculosis. The risk of extrapulmonary tuberculosis was higher among HIV-infected patients than among uninfected patients (adjusted odds ratio 5.14, 95% CI 1.04-24.5; p=0.045). 20 (26%) of 78 patients with tuberculosis were not diagnosed during their life and 13 (17%) had undiagnosed multidrug-resistant tuberculosis. Common comorbidities with tuberculosis were pyogenic pneumonia in 26 patients (33%) and anaemia in 15 (19%).

Interpretation: Increased clinical awareness and more proactive screening for tuberculosis and multidrug-resistant tuberculosis in inpatient settings are needed. Further autopsy studies are needed to ascertain the generalisability of the findings.

Abstract access 

Editor’s notes: This paper adds to the growing body of literature documenting a very high burden of tuberculosis (TB) in young adults, the majority of whom are HIV-positive, dying in hospitals in sub-Saharan Africa. Accurate knowledge of causes of death among people living with HIV is critical to developing strategies to reduce mortality. Although autopsies are the gold standard for identifying specific causes of death, autopsy data are sparse. In this study the authors undertook whole-body autopsies in medical inpatient deaths to describe the burden of TB. The GeneXpert MTB/RIF assay was used to assess the prevalence of multidrug-resistant tuberculosis.

The study achieved only 9% coverage of all deaths during the study period, similar to most other studies attempting full autopsy, which has poor acceptability to families. Among 125 included inpatients, the median time from admission to death was seven days. The majority of included people were HIV-positive, all diagnosed before death. The authors report a substantial burden of TB at autopsy, of which 26% (20/78) was only diagnosed after death and 17% (13/78) had undiagnosed multidrug-resistant (MDR) TB. None of the people with MDR-TB was on appropriate treatment. Bacterial pneumonia, found in over one-third of autopsies, was the next most common autopsy finding after TB.

The high burden of undiagnosed TB and MDR-TB at autopsy reported in this study highlights the need for routine screening for TB and MDR-TB among inpatients in TB endemic settings, and for measures to prevent in-hospital TB transmission. Rapid point-of-care diagnostics are necessary to enable early initiation of appropriate treatment. The study also highlights the key role of autopsy in identifying TB at death. This is consistently underestimated by physicians. Less invasive autopsy techniques based on multiple tissue biopsies are more acceptable to families and could have an important role in surveillance for TB as a cause of death. 

Avoid TB deaths
Africa
Zambia
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Barriers and facilitators of safer sexual behaviour for people living with HIV on ART

Intimacy versus isolation: a qualitative study of sexual practices among sexually active HIV-infected patients in HIV care in Brazil, Thailand, and Zambia.

Closson EF, Mimiaga MJ, Sherman SG, Tangmunkongvorakul A, Friedman RK, Limbada M, Moore AT, Srithanaviboonchai K, Alves CA, Roberts S, Oldenburg CE, Elharrar V, Mayer KH, Safren SA, HPTN063 study team. PLoS One. 2015 Mar 20;10(3):e0120957. doi: 10.1371/journal.pone.0120957. eCollection 2015.

The success of global treatment as prevention (TasP) efforts for individuals living with HIV/AIDS (PLWHA) is dependent on successful implementation, and therefore the appropriate contribution of social and behavioral science to these efforts. Understanding the psychosocial context of condomless sex among PLWHA could shed light on effective points of intervention. HPTN 063 was an observational mixed-methods study of sexually active, in-care PLWHA in Thailand, Zambia, and Brazil as a foundation for integrating secondary HIV prevention into HIV treatment. From 2010-2012, 80 qualitative interviews were conducted with PLWHA receiving HIV care and reported recent sexual risk. Thirty men who have sex with women (MSW) and 30 women who have sex with men (WSM) participated in equal numbers across the sites. Thailand and Brazil also enrolled 20 biologically-born men who have sex with men (MSM). Part of the interview focused on the impact of HIV on sexual practices and relationships. Interviews were recorded, transcribed, translated into English and examined using qualitative descriptive analysis. The mean age was 25 (SD = 3.2). There were numerous similarities in experiences and attitudes between MSM, MSW and WSM across the three settings. Participants had a high degree of HIV transmission risk awareness and practiced some protective sexual behaviors such as reduced sexual activity, increased use of condoms, and external ejaculation. Themes related to risk behavior can be categorized according to struggles for intimacy and fears of isolation, including: fear of infecting a sex partner, guilt about sex, sexual communication difficulty, HIV-stigma, and worry about sexual partnerships. Emphasizing sexual health, intimacy and protective practices as components of nonjudgmental sex-positive secondary HIV prevention interventions is recommended. For in-care PLWHA, this approach has the potential to support TasP. The overlap of themes across groups and countries indicates that similar intervention content may be effective for a range of settings.

Abstract   Full-text [free] access

Editor’s notes: Antiretroviral therapy has transformed the lives of many people living with HIV, holding the promise of sustaining health well into older age. Yet, as the authors of this paper remind us, HIV remains a stigmatised condition. Because of the fear and prejudice which continue to surround HIV, living with the infection while on antiretroviral therapy remains challenging not least because of its impact on intimate relationships. Using qualitative data from three very different cultural settings, the authors illustrate the continuing impact of HIV infection on the lives of people taking antiretroviral therapy. Many people in the study were keen to reduce the risk of infecting others through risky sexual behaviour. As a consequence, some struggled to establish and sustain intimate relationships trapped in feelings of shame about their infection and guilt about sexual enjoyment. The findings in this paper are not new. But what is interesting is how similar the experience of women and men living with HIV was across the different settings. As the health of more and more people living with HIV is sustained through antiretroviral therapy, there is a continuing and urgent need for programmes that address the fears and concerns that they may have about sexual behaviour. 

Africa, Asia, Latin America
Brazil, Thailand, Zambia
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Stigma, alcohol dependence and consulting traditional doctors associated with non-adherence to ART

Incomplete adherence among treatment-experienced adults on antiretroviral therapy in Tanzania, Uganda and Zambia.

Denison JA, Koole O, Tsui S, Menten J, Torpey K, van Praag E, Mukadi YD, Colebunders R, Auld AF, Agolory S, Kaplan JE, Mulenga M, Kwesigabo GP, Wabwire-Mangen F, Bangsberg DR. AIDS. 2015 Jan 28;29(3):361-71. doi: 10.1097/QAD.0000000000000543.

Objectives: To characterize antiretroviral therapy (ART) adherence across different programmes and examine the relationship between individual and programme characteristics and incomplete adherence among ART clients in sub-Saharan Africa.

Design: A cross-sectional study.

Methods: Systematically selected ART clients (≥18 years; on ART ≥6 months) attending 18 facilities in three countries (250 clients/facility) were interviewed. Client self-reports (3-day, 30-day, Case Index ≥48 consecutive hours of missed ART), healthcare provider estimates and the pharmacy medication possession ratio (MPR) were used to estimate ART adherence. Participants from two facilities per country underwent HIV RNA testing. Optimal adherence measures were selected on the basis of degree of association with concurrent HIV RNA dichotomized at less than or greater/equal to 1000 copies/ml. Multivariate regression analysis, adjusted for site-level clustering, assessed associations between incomplete adherence and individual and programme factors.

Results: A total of 4489 participants were included, of whom 1498 underwent HIV RNA testing. Nonadherence ranged from 3.2% missing at least 48 consecutive hours to 40.1% having an MPR of less than 90%. The percentage with HIV RNA at least 1000 copies/ml ranged from 7.2 to 17.2% across study sites (mean = 9.9%). Having at least 48 consecutive hours of missed ART was the adherence measure most strongly related to virologic failure. Factors significantly related to incomplete adherence included visiting a traditional healer, screening positive for alcohol abuse, experiencing more HIV symptoms, having an ART regimen without nevirapine and greater levels of internalized stigma.

Conclusion: Results support more in-depth investigations of the role of traditional healers, and the development of interventions to address alcohol abuse and internalized stigma among treatment-experienced adult ART patients.

Abstract access

Editor’s notes: Antiretroviral therapy (ART) non-adherence is a strong predictor of incomplete viral suppression, disease progression and mortality in people living with HIV. Declining adherence rates over long-term follow-up of people on ART have been illustrated in a number of observational studies in both low- and high-income settings. This multi-country study gives valuable insight into the challenges that treatment-experienced people living with HIV in low-income countries face on a daily basis. Incomplete adherence was found to be associated with a number of social and behavioural factors. These include internalised stigma, alcohol dependence, low levels of social support and consulting a traditional healer/herbalist. The factor most strongly associated with incomplete adherence was visiting a traditional healer because of HIV. The data contribute to the growing evidence on the role that traditional healers may have in care-seeking behaviours and influencing sustained ART adherence. Findings from this study corroborate research from other studies that alcohol abuse and HIV stigma are broad and consistent correlates of ART adherence. The study also highlights the variability of existing adherence measures and the need for accurate programme-level methods for assessing pill-taking behaviour in order to inform programme strategies and assess impact.

Improving adherence and thereby longer-term healthy outcomes for people living with HIV requires programmatic activities to address alcohol dependence and internalised stigma among treatment-experienced adults. Greater understanding of the role that traditional healers/herbalists play in how people living with HIV manage their infection is also needed to support life-long ART adherence in sub-Saharan Africa.

Africa
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Further evidence of an association with the injectable contraceptive, depot-medroxyprogesterone acetate with risk of HIV

Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis.

Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Karpoff S, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JH, Stalter R, Low N. PLoS Med. 2015 Jan 22;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. eCollection 2015.

Background: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.

Methods and findings: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37 124 women (43 613 woman-years) and 1830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship.

Conclusions: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Abstract  Full-text [free] access

Editor’s notes: As seen in the paper published this month by Ralph et al, observational studies have reported that hormonal contraception, in particular injectable progestins depot-medroxyprogesterone acetate (DMPA), may increase risk of HIV infection. This individual patient data meta-analysis adds further to the evidence. A major strength of the study is the large sample size. It provides sufficient power to examine associations between specific contraceptives and HIV risk and to investigate effect modification in pre-specified sub-group analyses. Furthermore, using individual-level data allowed a consistent approach to coding and adjustment for confounding. If the association is real, this has important implications for sexual and reproductive health in areas of sub-Saharan Africa where the incidence of HIV acquisition and unintended pregnancy is high.

 


 

Hormonal contraceptive use and women's risk of HIV acquisition: a meta-analysis of observational studies.

Ralph LJ, McCoy SI, Shiu K, Padian NS. Lancet Infect Dis. 2015 Jan 8. pii: S1473-3099(14)71052-7. doi: 10.1016/S1473-3099(14)71052-7. [Epub ahead of print]

Background: The evidence from epidemiological research into whether use of hormonal contraception increases women's risk of HIV acquisition is inconsistent. We did a robust meta-analysis of existing data to provide summary estimates by hormonal contraceptive method which can be used to inform contraceptive guidelines, models, and future studies.

Methods: We updated a recent systematic review to identify and describe studies that met inclusion criteria. To ensure inclusion of more recent research, we searched PubMed for articles published after December, 2011, using the terms "hormonal contraception", "HIV/acquisition", "injectables", "progestin", and "oral contraceptive pills". We assessed statistical heterogeneity for these studies, and, when appropriate, combined point estimates by hormonal contraception formulation using random-effects models. We assessed publication bias and investigated heterogeneity through subgroup and stratified analyses according to study population and design features.

Findings: We identified 26 studies, 12 of which met inclusion criteria. There was evidence of an increase in HIV risk in the ten studies of depot medroxyprogesterone acetate (pooled hazard ratio [HR] 1.40, 95% CI 1.16-1.69). This risk was lower in the eight studies done in women in the general population (pooled HR 1.31, 95% CI 1.10-1.57). There was substantial between-study heterogeneity in secondary analyses of trials (n=7, I2 51.1%, 95% CI 0-79.3). Although individual study estimates suggested an increased risk, substantial heterogeneity between two studies done in women at high risk of HIV infection (I2 54%, 0-88.7) precluded pooling estimates. There was no evidence of an increased HIV risk in ten studies of oral contraceptive pills (pooled HR 1.00, 0.86-1.16) or five studies of norethisterone enanthate (pooled HR 1.10, 0.88-1.37).

Interpretation: Our findings show a moderate increased risk of HIV acquisition for all women using depot medroxyprogesterone acetate, with a smaller increase in risk for women in the general population. Whether the risks of HIV observed in our study would merit complete withdrawal of depot medroxyprogesterone acetate needs to be balanced against the known benefits of a highly effective contraceptive.

Abstract access

Editor’s notes: This meta-analysis has similar findings to the individual patient data (IPD) meta-analysis by Morrison et al, also published this month. The study finds that depot medroxyprogesterone (DMPA) is associated with a moderate increase in HIV risk, and little evidence of a risk associated with combined oral contraceptives or norethisterone enanthate (NET-EN). The policy implications of this finding are unclear. As with the IPD analysis, this meta-analysis is based on observational studies and does not provide conclusive evidence that DMPA causes the increased risk of HIV. However, it does provide refined estimates for modelling studies to assess the implications of possible withdrawal of DMPA on maternal and HIV-associated mortality, so that context-specific contraceptive policies can be considered.

Africa
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Optimising outcomes on second-line antiretroviral therapy: partner-based modified directly observed therapy is not the answer

Partner-based adherence intervention for second-line antiretroviral therapy (ACTG 5234): a multinational randomised trial.

Gross R, Zheng L, La Rosa A, Sun X, Rosenkrantz SL, Wagner Cardoso S, Ssali F, Camp R, Godfrey C, Cohn SE, Robbins GK, Chisada A, Wallis CL, Reynolds NR, Lu D, Safren SA, Hosey L, Severe P, Collier AC for the ACTG 5234 team. Lancet HIV 2015; 2: e12–19

Background: Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV-infected patients for whom first-line therapy had failed.

Methods: We did a multicentre, international, randomised clinical trial at nine sites in Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, and Zimbabwe. Participants aged 18 years or older for whom first-line therapy had failed, with HIV RNA concentrations greater than 1000 copies per mL and with a willing partner, were randomly assigned (1:1), via computer-generated randomisation, to receive partner-based modified directly observed therapy or standard of care. Randomisation was stratified by screening HIV RNA concentration (≤10 000 copies per mL vs >10 000 copies per mL). Participants and site investigators were not masked to group assignment. Primary outcome was confirmed virological failure (viral load >400 copies per mL) by week 48. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00608569.

Findings: Between April 23, 2009, and Sept 29, 2011, we randomly assigned 259 participants to the modified directly observed therapy group (n=129) or the standard-of-care group (n=130). 34 (26%) participants in the modified directly observed therapy group achieved the primary endpoint of virological failure by week 48 compared with 23 (18%) participants in the standard-of-care group. The Kaplan-Meier estimated cumulative probability of virological failure by week 48 was 25·1% (95% CI 17·7–32·4) in the modified directly observed therapy group and 17·3% (10·8–23·7) in the standard-of-care group, for a weighted difference in standard of care versus modified directly observed therapy of −6·6% (95% CI −16·5% to 3·2%; p=0·19). 36 (14%) participants reported at least one grade 3 or higher adverse event or laboratory abnormality (n=21 in the modified directly observed therapy group and n=15 in the standard-of-care group).

Interpretation: Partner-based training with modified directly observed therapy had no effect on virological suppression. The intervention does not therefore seem to be a promising strategy to increase adherence. Intensive follow-up with clinic staff might be a viable approach in this setting.

Abstract access

Editor’s notes: High rates of virologic failure on second-line antiretroviral therapy (ART) are reported in resource-limited settings. The main driver of this is thought to be sub-optimal adherence rather than resistance. As many of these settings have limited access to third-line regimens there is an urgent need for evidence-informed programmes to optimise peoples’ adherence, both to first-line and second-line regimens.

The results from this randomised controlled trial provide further evidence that partner-based modified directly observed therapy is not the answer. Interestingly, people enrolled in this trial had far lower rates of virologic failure than have been observed in programmatic settings, regardless of whether they were in the programme or standard-of-care arm. Many factors could account for this, including the fact that all people enrolled in the study had to have disclosed their status to a friend or family member, all received enhanced education and support and all attended regular clinic appointments. Further pragmatic studies which focus on clinic-and patient-level programmes are needed to determine the optimal strategies for maximising peoples’ adherence. 

Africa, Latin America
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