Articles tagged as "Zimbabwe"

Task-shifting reduces costs for early infant male circumcision

Comparative cost of early infant male circumcision by nurse-midwives and doctors in Zimbabwe.

Mangenah C, Mavhu W, Hatzold K, Biddle AK, Ncube G, Mugurungi O, Ticklay I, Cowan FM, Thirumurthy H. Glob Health Sci Pract. 2016 Jul 13;4 Suppl 1:S68-75. doi: 10.9745/GHSP-D-15-00201. Published online 2016 Jul 2.

Background: The 14 countries that are scaling up voluntary male medical circumcision (VMMC) for HIV prevention are also considering early infant male circumcision (EIMC) to ensure longer-term reductions in HIV incidence. The cost of implementing EIMC is an important factor in scale-up decisions. We conducted a comparative cost analysis of EIMC performed by nurse-midwives and doctors using the AccuCirc device in Zimbabwe.

Methods: Between August 2013 and July 2014, nurse-midwives performed EIMC on 500 male infants using AccuCirc in a field trial. We analyzed the overall unit cost and identified key cost drivers of EIMC performed by nurse-midwives and compared these with costing data previously collected during a randomized noninferiority comparison trial of 2 devices (AccuCirc and the Mogen clamp) in which doctors performed EIMC. We assessed direct costs (consumable and nonconsumable supplies, device, personnel, associated staff training, and waste management costs) and indirect costs (capital and support personnel costs). We performed one-way sensitivity analyses to assess cost changes when we varied key component costs.

Results: The unit costs of EIMC performed by nurse-midwives and doctors in vertical programs were US$38.87 and US$49.77, respectively. Key cost drivers of EIMC were consumable supplies, personnel costs, and the device price. In this cost analysis, major cost drivers that explained the differences between EIMC performed by nurse-midwives and doctors were personnel and training costs, both of which were lower for nurse-midwives.

Conclusions: EIMC unit costs were lower when performed by nurse-midwives compared with doctors. To minimize costs, countries planning to scale up EIMC should consider using nurse-midwives, who are in greater supply than doctors and are the main providers at the primary health care level, where most infants are born.

Abstract  Full-text [free] access 

Editor’s notes: The evidence behind the efficacy for male circumcision in HIV prevention has been proven beyond a reasonable doubt, and 14 countries with a high HIV prevalence are currently scaling up voluntary medical male circumcision. To improve future HIV prevention, WHO and UNICEF also recommend that early infant male circumcision be performed within the first 60 days of life in countries with a high HIV prevalence. In countries such as Zimbabwe, an acute shortage of human resources for health has the potential to hinder scale-up of early infant male circumcision.  However, with new devices such as the AccuCirc® , early infant male circumcision can be performed without advanced surgical skills – raising the potential for task shifting as a way to alleviate pressure on human resources.  

This study compares the unit cost of early infant male circumcision using the AccuCirc® , as performed by doctors and by nurse-midwives. Nurse-midwives on average took a longer time to complete a circumcision (average 18 minutes) as compared to doctors (average 16 minutes).  However, the reductions in salary costs offset this increased time, reducing the unit cost of early infant male circumcision overall. Integrating early infant male circumcision into a public health facility (as compared to a vertical programme) would further reduce the costs. 

This study suggests that countries seeking to scale up early infant male circumcision should consider task shifting as a way to reduce costs. Task shifting does pose the risk of increasing workload for lower-level personnel; more nurse-midwives will need to be trained to cope with additional responsibilities to avoid over-burdening existing personnel. However, this is a promising solution to enable scale-up of early infant male circumcision quickly and affordably in settings such as Zimbabwe.

Africa
Zimbabwe
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Immediate initiation of HIV treatment is cost-effective, but needs a large portion of health system spending

Changing HIV treatment eligibility under health system constraints in sub-Saharan Africa: Investment needs, population health gains, and cost-effectiveness.

Hontelez JA, Chang AY, Ogbuoji O, Vlas SJ, Barnighausen T, Atun R. AIDS. 2016 Jun 29. [Epub ahead of print]

Objective: We estimated the investment need, population health gains, and cost-effectiveness of different policy options for scaling-up prevention and treatment of HIV in the 10 countries that currently comprise 80% of all people living with HIV in sub-Saharan Africa (Ethiopia, Kenya, Malawi, Mozambique, Nigeria, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe).

Design: We adapted the established STDSIM model, to capture the health system dynamics: demand-side and supply-side constraints in the delivery of antiretroviral treatment (ART).

Methods: We compared different scenarios of supply-side (i.e. health system capacity) and demand-side (i.e. health seeking behavior) constraints, and determined the impact of changing guidelines to ART eligibility at any CD4 cell count within these constraints.

Results: Continuing current scale-up would require US$178 billion by 2050. Changing guidelines to ART at any CD4 cell count is cost-effective under all constraints tested in the model, especially in demand-side constrained health systems because earlier initiation prevents loss to follow-up of patients not yet eligible. Changing guidelines under current demand-side constraints would avert 1.8 million infections at US$208 per life-year saved.

Conclusions: Treatment eligibility at any CD4 cell count would be cost-effective, even under health system constraints. Excessive loss to follow up and mortality in patients not eligible for treatment can be avoided by changing guidelines in demand-side constrained systems. The financial obligation for sustaining the AIDS response in sub-Saharan Africa over the next 35 years is substantial, and requires strong, long-term commitment of policy makers and donors to continue to allocate substantial parts of their budgets.

Abstract access

Editor’s notes: Recent WHO guidelines recommend that everyone who is diagnosed as HIV positive should be allowed to start treatment immediately, a change to the former guideline where their CD4 count (a measure of disease progression) was the main criteria for starting treatment. This paper uses a model to look at the costs and benefits of changing to this immediate treatment regimen in the sub-Saharan African countries most affected by the epidemic. The authors find that allowing all HIV people living with HIV to access treatment is cost-effective, and this finding does not change when the model assumptions are varied. However, the impact of this change on the health system budgets in these countries is very substantial, and the authors suggest that a large commitment is necessary from policymakers and donors to sustain this response as short-term spending will not be enough to make an impact.

Africa
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Antiretroviral therapy: being reborn into uncertainty

What will become of me if they take this away? Zimbabwean women's perceptions of "free" ART.

Gona CM, McGee E, DeMarco R. J Assoc Nurses AIDS Care. 2016 May 13. pii: S1055-3290(16)30040-1. doi: 10.1016/j.jana.2016.05.001. [Epub ahead of print]

The evolution of antiretroviral therapies (ART) has redefined HIV infection from a life-threatening disease to a chronic manageable condition. Despite ART, HIV infection remains a serious health burden in Zimbabwe, particularly among women of reproductive age. In this interpretive phenomenology study, we interviewed 17 women with advanced HIV infection to uncover and understand their experiences of living with HIV infection in the ART era. Two themes (knowing the restorative power of ART and the heavy burden of being infected with HIV) reflected the women's experiences. ART brought physical and mental relief, but did not change the sobering reality of poverty or the challenges posed by the infective nature of HIV. The heavily donor-funded Zimbabwean ART program has been a success story, but there is uncertainty over its long-term sustainability. In resource-limited countries, clinicians and other stakeholders should continue to focus on HIV prevention as the cornerstone of HIV programming.

Abstract access

Editor’s notes: In Zimbabwe, as in much of sub-Saharan Africa, women are disproportionately affected by HIV infection. In 2013, women comprised 59% of adults living with HIV. Between 2007 and 2010, women accounted for 64% of people enrolled on ART in the country. Currently only 77% of women in clinical need of ART have access to it with most accessing it through a government and donor-funded ‘cost-free’ programme.  For women in Zimbabwe, living with HIV infection, normal life not only depends on the assurance of uninterrupted access to ART, but also the ability to get married and bear children.

The authors of this paper report on Zimbabwean women’s experiences of living with HIV infection while on ART. The study was nested within an ongoing clinical trial. Women were interviewed through in-depth, individual, face-to-face, open-ended interviews. 

The authors identify a number of important implications of the findings of this study. First, many women, in addition to concerns about their health, also had to contend with the effects of extreme poverty and gender inequality. For HIV treatment programmes to be successful, health care providers and policy makers should incorporate poverty reduction and gender equity components. Second, funding provisions should be put in place to ensure continued supplies of medications in order to reduce the reliance on external donor funding. Third, there is a need to clarify and strengthen policies regarding the continuation of treatment after the completion of a clinical trial to ensure participants’ continued access. Fourth, given the ability of ART to transform HIV into a chronic disease, reproductive health service provision should be prioritized to enable people living with HIV to have children if they wish. Further, and particularly in the light of these challenges, HIV prevention should be centralised as a focal point of HIV programming in order to reduce HIV incidence.

Africa
Zimbabwe
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Substantial morbidity despite preserved CD4 count in children with slow-progressing HIV

Chronic morbidity among older children and adolescents at diagnosis of HIV infection.

McHugh G, Rylance J, Mujuru H, Nathoo K, Chonzi P, Dauya E, Bandason T, Simms V, Kranzer K, Ferrand RA. J Acquir Immune Defic Syndr. 2016 May 11. [Epub ahead of print]. doi: 10.1097/QAI.0000000000001073

Background: Substantial numbers of children with HIV present to health care services in older childhood and adolescence, previously undiagnosed. These "slow-progressors" may experience considerable chronic ill-health, which is not well-characterised. We investigated the prevalence of chronic morbidity among children aged 6-15 years at diagnosis of HIV infection.

Methods: A cross sectional study was performed at seven primary care clinics in Harare, Zimbabwe. Children aged 6-15 years who tested HIV positive following provider-initiated HIV testing and counselling were recruited. A detailed clinical history and standardised clinical examination was undertaken. The association between chronic disease and CD4 count was investigated using multivariate logistic regression.

Results: Of the 385 participants recruited (52% female, median age 11 years (IQR 8-13)), 95% were perinatally HIV-infected. The median CD4 count was 375 (IQR 215-599) cells/mm3. Although 78% had previous contact with health care services, HIV testing had not been performed. There was a high burden of chronic morbidity: 23% were stunted, 21% had pubertal delay, 25% had chronic skin disease, 54% had a chronic cough of more than 1 month's duration, 28% had abnormal lung function and 12% reported hearing impairment. There was no association between CD4 count of <500cells/mm3 or <350 cells/mm3 with WHO stage or these chronic conditions.

Conclusion: In children with slow-progressing HIV, there is a substantial burden of chronic morbidity even when CD4 count is relatively preserved. Timely HIV testing and prompt ART initiation are urgently needed to prevent development of chronic complications.

Abstract  Full-text [free] access

Editor’s notes: Substantial numbers of infants who have perinatally acquired HIV are presenting with HIV infection in later childhood or adolescence. It is estimated that a third of infants living with HIV are ‘slow-progressors’ with a median survival of 16 years. This study found a large burden of chronic morbidity among older children and adolescent at the time of HIV diagnosis.   Interestingly, no association between CD4 count and WHO HIV disease stage was seen. Children with slow-progressing disease still appear go on to develop poor growth and chronic lung and skin disease despite preserved CD4 counts. Up until recently many of these children would not have been eligible to start ART based on the WHO 2013 HIV treatment guidelines. Recent changes to WHO guidelines recommending immediate ART for all, including older children, will hopefully reduce the risk of development of chronic complications in this population. Improved outcomes will only occur with timely diagnosis which requires increasing awareness of the burden of undiagnosed HIV disease, strengthening provider-initiated HIV testing and counselling and improving retention in ART care in this vulnerable age group.

Africa
Zimbabwe
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Routine programmatic data used to estimate HIV incidence and service uptake among female sex workers in Zimbabwe

Implementation and operational research: cohort analysis of program data to estimate HIV incidence and uptake of HIV-related services among female sex workers in Zimbabwe, 2009-2014.

Hargreaves JR, Mtetwa S, Davey C, Dirawo J, Chidiya S, Benedikt C, Naperiela Mavedzenge S, Wong-Gruenwald R, Hanisch D, Magure T, Mugurungi O, Cowan FM. J Acquir Immune Defic Syndr. 2016 May 1;72(1):e1-8. doi: 10.1097/QAI.0000000000000920.

Background: HIV epidemiology and intervention uptake among female sex workers (FSW) in sub-Saharan Africa remain poorly understood. Data from outreach programs are a neglected resource.

Methods: Analysis of data from FSW consultations with Zimbabwe's National Sex Work program, 2009-2014. At each visit, data were collected on sociodemographic characteristics, HIV testing history, HIV tests conducted by the program and antiretroviral (ARV) history. Characteristics at first visit and longitudinal data on program engagement, repeat HIV testing, and HIV seroconversion were analyzed using a cohort approach.

Results: Data were available for 13 360 women, 31 389 visits, 14 579 reported HIV tests, 2750 tests undertaken by the program, and 2387 reported ARV treatment initiations. At first visit, 72% of FSW had tested for HIV; 50% of these reported being HIV positive. Among HIV-positive women, 41% reported being on ARV. 56% of FSW attended the program only once. FSW who had not previously had an HIV-positive test had been tested within the last 6 months 27% of the time during follow-up. After testing HIV positive, women started on ARV at a rate of 23/100 person years of follow-up. Among those with 2 or more HIV tests, the HIV seroconversion rate was 9.8/100 person years of follow-up (95% confidence interval: 7.1 to 15.9).

Conclusions: Individual-level outreach program data can be used to estimate HIV incidence and intervention uptake among FSW in Zimbabwe. Current data suggest very high HIV prevalence and incidence among this group and help identify areas for program improvement. Further methodological validation is required.

Abstract access

Editor’s notes: Female sex workers in resource poor regions have been shown to have higher levels of HIV incidence and prevalence than people in the general population. Due to the highly stigmatised and often illegal nature of their work, these individuals are often marginalised in society. This can lead to poor engagement with the HIV testing and treatment programmes provided for the general population. Targeted outreach programmes for female sex workers such as the “Sisters for Change” programme in Zimbabwe described in this paper, aim to improve the engagement with testing and care for this group.

Collecting reliable data from female sex workers using a convenience sampling approach in order to estimate the prevalence of HIV is challenging due to the difficulty in ensuring the survey sample is representative of the wider female sex worker population. An alternative approach is respondent driven sampling (RDS) in which respondents recruit their peers to produce a generally representative sample of hard-to-reach populations. The results from RDS are however complex to analyse and interpret.

This paper presents an alternative approach using routinely collected data. Using the dates of programme visits, HIV tests (conducted both within and outside of the programme) and dates of antiretroviral initiation, the researchers generated estimates of HIV prevalence (number of positive tests/total number of tests) and HIV incidence (time at risk calculated from the first visit to an imputed date of seroconversion). They also identified risk factors associated with socio-demographic parameters or HIV testing history that were associated with a failure to continue engagement with the programme after a first visit. The prevalence and incidence results are consistent with results from a series of RDS surveys previously conducted in Zimbabwe by this research team.

A difficulty highlighted by the authors is that while this method improves on convenience sampling, it is still difficult to know how HIV incidence and prevalence among programme participants compares to that in the wider female sex worker population. 

In summary this paper presents an approach by which similar programmes elsewhere could make better use of routinely collected data in order to generate estimates of impact and also identify sub-groups of female sex workers with poorer engagement with care. This in turn could lead to a more effective targeting of limited resources.

Africa
Zimbabwe
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Oral PrEP reduces risk of HIV and does not result in riskier sex

Effectiveness and safety of oral HIV pre-exposure prophylaxis (PrEP) for all populations: A systematic review and meta-analysis.

Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly K R, Koechlin FM, Rodolph M, Hodges-Mameletzis I, Grant RM. AIDS. 2016 May 5. [Epub ahead of print]

Objective: Pre-exposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate (TDF) as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes.

Design: Rigorous systematic review and meta-analysis.

Methods: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis.

Results: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared to placebo. Trials with PrEP use >70% demonstrated the highest PrEP effectiveness (RR = 0.30, 95% CI: 0.21-0.45, p < 0.001) compared to placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness.

Conclusion: PrEP is protective against HIV infection across populations, presents few significant safety risks, and no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV-risk.

Abstract access

Editor’s notes: This systematic review is the first to aggregate data from across oral pre-exposure prophylaxis (PrEP) studies, including randomized control trials and observational studies, to present clear evidence on the effectiveness of oral PrEP use. The findings confirm that oral PrEP significantly reduces the risk of acquiring HIV if taken consistently and correctly across populations, countries, and most age groups. Differences in efficacy directly correlate with adherence, which accounts for the lower efficacy seen in some subgroups. Perhaps two of the most compelling analyses presented in this paper relate to resistance and behavioural disinhibition. The risk of resistance was shown to be quite low, and study participants exhibiting resistant HIV either enrolled in the studies during an acute infection stage or acquired resistant strains during the course of the research. Regarding behavioural disinhibition, indicators measured such as rates of sexually transmitted infections revealed that PrEP use in the efficacy trials was not associated with behavioural disinhibition and in some studies, resulted in even safer sexual behaviour than what was reported at baseline. Recently completed demonstration projects have reported increased rates of STIs among gay men and other men who have sex with men. However, in the open-label extensions included in this review, where counselling was more intensive, safer sex practices were maintained, thus suggesting that counselling can be effective in preventing behavioural disinhibition. 

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Profound effect of ART on mortality through reduction of opportunistic infections

Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low and middle income countries: a systematic review and meta-analysis. 

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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The conundrum of future funding for HIV – who pays and how?

Long-term financing needs for HIV control in sub-Saharan Africa in 2015-2050: a modelling study. 

Atun R, Chang AY, Ogbuoji O, Silva S, Resch S, Hontelez J, Barnighausen T. BMJ Open. 2016 Mar 6;6(3):e009656. doi: 10.1136/bmjopen-2015-009656.

Objectives: To estimate the present value of current and future funding needed for HIV treatment and prevention in 9 sub-Saharan African (SSA) countries that account for 70% of HIV burden in Africa under different scenarios of intervention scale-up. To analyse the gaps between current expenditures and funding obligation, and discuss the policy implications of future financing needs.

Design: We used the Goals module from Spectrum, and applied the most up-to-date cost and coverage data to provide a range of estimates for future financing obligations. The four different scale-up scenarios vary by treatment initiation threshold and service coverage level. We compared the model projections to current domestic and international financial sources available in selected SSA countries.

Results: In the 9 SSA countries, the estimated resources required for HIV prevention and treatment in 2015-2050 range from US$98 billion to maintain current coverage levels for treatment and prevention with eligibility for treatment initiation at CD4 count of <500/mm3 to US$261 billion if treatment were to be extended to all HIV-positive individuals and prevention scaled up. With the addition of new funding obligations for HIV–which arise implicitly through commitment to achieve higher than current treatment coverage levels–overall financial obligations (sum of debt levels and the present value of the stock of future HIV funding obligations) would rise substantially.

Conclusions: Investing upfront in scale-up of HIV services to achieve high coverage levels will reduce HIV incidence, prevention and future treatment expenditures by realising long-term preventive effects of ART to reduce HIV transmission. Future obligations are too substantial for most SSA countries to be met from domestic sources alone. New sources of funding, in addition to domestic sources, include innovative financing. Debt sustainability for sustained HIV response is an urgent imperative for affected countries and donors

Abstract  Full-text [free] access 

Editor’s notes: The authors of this interesting paper use the most up-to-date cost and coverage data to provide a range of estimates for future treatment financing obligations. Epidemiological parameters are included to fit the Goals model and key prevention services such as ‘prevention of mother-to-child HIV transmission’ and ‘voluntary medical male circumcision’ are also included.

Financing needs for the nine countries are estimated by varying treatment initiation threshold (everyone initiated on treatment versus initiation at CD4 of <500cells/mm3) and/or coverage level for prevention and treatment (‘current’ levels and a ‘scale up’ scenario). The authors also attempt to assess both the ethics and the cost of different approaches.

For all scenarios, there is a steady decline in proportion of treatment costs and an increase in the proportion of prevention costs. This apparent contradiction is largely because there will be fewer individuals on treatment over time but prevention costs rise because they are mostly invested in non-infected populations, which increases with population growth.

In the nine countries, estimated resources required for HIV prevention and treatment from 2015-2050 will be large. This is increased further when human resources and supplies increase at the rate of GDP per capita.

However, there is undoubtedly an ethical responsibility to not only continue financing people receiving ART, but, that the responsibility extends to people in equal need who are not on treatment. The ethics is underpinned by the evidence. This illustrates how ‘front-loading’ investments in HIV scale-up now to ensure high levels of coverage, will significantly reduce future HIV incidence and prevalence. 

Africa
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Near-patient TB test reduces hospital deaths in HIV-positive adults

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. 

Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, Mehta N, Calligaro G, Lombard CJ, Kadzirange G, Bandason T, Chansa A, Liusha N, Mangu C, Mtafya B, Msila H, Rachow A, Hoelscher M, Mwaba P, Theron G, Dheda K. Lancet. 2016 Mar 19;387(10024):1187-97. doi: 10.1016/S0140-6736(15)01092-2. Epub 2016 Mar 10.

Background: HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.

Methods: We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weight loss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730.

Findings: Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0.83 (95% CI 0.73-0.96), p=0.012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0.82 [95% CI 0.70-0.96], p=0.015). No adverse events were associated with LAM testing.

Interpretation: Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital in-patients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum.

Abstract access  

Editor’s notes: TB is a leading cause of hospitalization and in-hospital death among people living with HIV worldwide. This randomised controlled trial in southern Africa provides strong evidence of the impact of a simple, urine-based test in HIV-positive adults admitted to hospital with symptoms of TB. Use of the lateral flow lipoarabinomannan (LAM) test, in addition to a package of routine TB diagnostic tests, led to a modest reduction in all-cause mortality. This reduction in mortality occurred despite only a small increase in the proportion starting TB treatment, suggesting that LAM testing might have enabled more precision in the identification of people with TB.

Half of all deaths occurred in people with CD4 cell count ≤50 cells/µL and the impact of the urinary LAM test was greatest in this group, as suggested by previous studies. This may lead to strengthening of WHO policy recommendations to use the lateral flow LAM test to assist with TB diagnosis in people admitted to hospital with advanced HIV and with symptoms and signs of TB. There is still no strong evidence to suggest a role for LAM testing at more peripheral levels of the health system or in people who are not seriously ill.

The heterogeneity in effect between countries is notable, although the trial was not powered to detect mortality differences at each site. The availability and use of other diagnostics (which could include sputum smear microscopy, Xpert®, chest X-ray, ultrasound and computed tomography), and the level of physician input in clinical management, differed substantially across sites and could have modified the effect of LAM testing. Additional exploration of data from this trial and from other ongoing studies should help to further define the role of urine LAM in the TB diagnostic bundle in different health care settings.

Africa
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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. 

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, Adult ACTGAST. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert® MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

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Editor’s notes: Tuberculosis (TB) remains the leading cause of death among HIV-positive people worldwide. Existing diagnostic tests for TB lack sensitivity, particularly among HIV-positive people, and autopsy studies consistently illustrate that TB is common at death, but often not identified prior to death. This has led to questions about whether empirical TB treatment, meaning treatment for TB in the absence of bacteriological confirmation, should be more widely used among HIV-positive people.

This trial compared empirical TB treatment to isoniazid preventive therapy among adult outpatients with very low CD4 counts starting antiretroviral therapy (ART). People could be enrolled in the study if they did not have confirmed or suspected TB based on symptoms, locally-accessible diagnostic tests (including chest radiography and sputum smear) and, when available, testing with Xpert® MTB/RIF. There was no difference in mortality at six months between participants given empirical TB treatment compared to isoniazid preventive therapy. Mortality was remarkably low overall, particularly considering that participants had very low CD4 counts. It seems likely that the enrolment criteria excluded people at highest risk of death from participating in the study.

Screening for TB at the time of starting ART could reduce mortality if the tests are sufficiently sensitive, and if people identified to have TB receive effective treatment. However, this study was not designed to address how best to do this in resource-limited settings, where chest radiography and Xpert® MTB/RIF are often not accessible. This study does suggest that isoniazid preventive therapy can be given at the time of ART initiation among people who have been effectively screened for TB. The results of other studies of empirical TB treatment, with different designs in different populations, are awaited. Data from all these studies together may provide evidence to guide the optimal package of care for people presenting with advanced HIV disease. 

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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