Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment. Conclusions: Improved access to and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear.

In a population-based representative sample of adults residing in 22 communities in Botswana, a southern African country with high HIV prevalence, 1 in 4 individuals had high blood pressure. High blood pressure was less prevalent in adults with HIV than without HIV. Sixty percent of persons with high blood pressure had not previously been diagnosed. Among individuals with a prior diagnosis of high blood pressure who reported being prescribed anti-hypertension medications, almost half had elevated blood pressure, irrespective of HIV-status. One-third of adults in this setting (mainly men) declined free non-invasive blood pressure assessments in their households. In conclusion, our study highlights alarmingly high hypertension rates in the community, with low levels of awareness and control, emphasizing the urgent need for community level BP screening and active management to reach recommended targets.

Accurate HIV and CD4 testing are critical in program implementation, with HIV misdiagnosis having serious consequences at both the client and/or community level. We implemented a comprehensive training and Quality Assurance (QA) program to ensure accuracy of point-of-care HIV and CD4 count testing by lay counsellors during the Botswana Combination Prevention Project (BCPP). We compared the performance of field testing by lay counselors to results from an accredited laboratory to ascertain accuracy of testing. All trained lay counselors passed competency assessments and performed satisfactorily in proficiency testing panel evaluations in 2013, 2014, and 2015. There was excellent agreement (99.6%) between field and laboratory-based HIV test results; of the 3002 samples tested, 960 and 2030 were concordantly positive and negative respectively, with 12 misclassifications (kappa score 0.99, p < 0.0001). Of the 149 HIV-positive samples enumerated for CD4 count in the field using PIMA at a threshold of 350 cells/L; there was 86% agreement with laboratory testing, with only 21 misclassified. The mean difference between field and lab CD4 testing was -16.16 cells/L (95% CI -5.4 - 26.9). Overall, there was excellent agreement between field and laboratory results for both HIV rapid test and PIMA CD4 results. A standard training package to train lay counselors to accurately perform HIV and CD4 point-of-care testing in field settings was feasible, with point-of-care results obtained by lay counselors comparable to laboratory-based testing.

Background: Cryptococcal antigen (CrAg) screening in individuals with advanced HIV reduces cryptococcal meningitis (CM) cases and deaths. The World Health Organization recently recommended increasing screening thresholds from CD4 ≤100 cells/µL to ≤200 cells/µL. CrAg screening at CD4 ≤100 cells/µL is cost-effective; however, the cost-effectiveness of screening patients with CD4 101-200 cells/µL requires evaluation. Methods: Using a decision analytic model with Botswana-specific cost and clinical estimates, we evaluated CrAg screening and treatment among individuals with CD4 counts of 101-200 cells/µL. We estimated the number of CM cases and deaths nationally and treatment costs without screening. For screening we modeled the number of CrAg tests performed, number of CrAg-positive patients identified, proportion started on pre-emptive fluconazole, CM cases and deaths. Screening and treatment costs were estimated and cost per death averted or disability-adjusted life year (DALY) saved compared with no screening. Results: Without screening, we estimated 142 CM cases and 85 deaths annually among individuals with CD4 101-200 cells/µL, with treatment costs of $368,982. With CrAg screening, an estimated 33,036 CrAg tests are performed, and 48 deaths avoided (1,017 DALYs saved).  While CrAg screening costs an additional $155,601, overall treatment costs fall by $39,600 (preemptive and hospital-based CM treatment), yielding a net increase of $116,001. Compared to no screening, high coverage of CrAg screening and pre-emptive treatment for CrAg-positive individuals in this population avoids one death for $2440 and $114 per DALY saved. In sensitivity analyses assuming a higher proportion of antiretroviral therapy (ART)-naïve patients (75% versus 15%), cost per death averted was $1472; $69 per DALY saved. Conclusions: CrAg screening for individuals with CD4 101-200 cells/µL was estimated to have a modest impact, involve additional costs, and be less cost-effective than screening populations with CD4 counts ≤100 cells/µL. Additional CrAg screening costs must be considered against other health system priorities.

The UNAIDS target to reduce HIV-related death to fewer than 500 000 deaths per year by 2020 will not be met.1 This statement might not be headline grabbing as this target was never as prominent as the 90-90-90 targets,2 the achievement of which is a necessary but not sufficient step towards ending AIDS mortality. | | The decline in HIV-related deaths is too slow. Early initiation of antiretroviral therapy (ART) for people living with HIV is the most important intervention for reducing HIV-related deaths. Access to ART for all is a distant goal in some settings due to ongoing challenges in identifying people with HIV and getting them on to treatment1 and ART alone isn’t enough to fully address HIV-related deaths. Among adults and adolescents, advanced HIV disease is diagnosed as a CD4 count of fewer than 200 cells per μL or a WHO stage 3 or 4 event.3 Evidence from South Africa shows more advanced HIV disease among ART-experienced people than among ART-naive people.4 Efforts to prevent disease progression will never replace the need for parallel improvements in the treatment of opportunistic infections.

BACKGROUND: Ensuring that individuals who are living with HIV rapidly initiate antiretroviral therapy (ART) is an essential step in meeting the 90-90-90 targets. We evaluated the feasibility and outcomes of rapid ART initiation in the Botswana Combination Prevention Project (BCPP). We aimed to establish whether simplified ART initiation with the offer of same-day treatment could increase uptake and reduce time from clinic linkage to treatment initiation, while maintaining rates of retention in care and viral suppression. METHODS: We did a quasi-experimental before and after study with use of data from the BCPP. The BCPP was a community-randomised HIV-prevention trial done in 30 communities across Botswana from Oct 1, 2013, to June 30, 2018. Participants in the 15 intervention clusters, who were HIV-positive and not already taking ART were offered universal HIV-treatment and same-day ART with a dolutegravir-based regimen at first clinic visit. This rapid ART intervention was implemented mid-way through the trial on June 1, 2016, enabling us to determine the effect of rapid ART guidelines on time to ART initiation and rates of retention in care and viral suppression at 1 year in the BCPP intervention group. FINDINGS: We assessed 1717 adults linked to study clinics before rapid ART introduction and 800 after rapid ART introduction. During the rapid ART period, 457 (57·1%, 95% CI 53·7-60·6) individuals initiated ART within 1 day of linkage, 589 (73·7%, 70·6-76·7) of 799 within 1 week, 678 (84·9%, 82·4-87·3) of 799 within 1 month, and 744 (93·5%, 91·6-95·1) of 796 within 1 year. Before the introduction of rapid ART, 163 (9·5%, 95% CI 8·2-11·0) individuals initiated ART within 1 day of linkage, 276 (16·1%, 14·4-17·9) within 1 week, 839 (48·9%, 46·5-51·3) within 1 month, and 1532 (89·2%, 87·7-90·6) within 1 year. 1 year after ART initiation, 1472 (90·5%, 87·4-92·8) of 1627 individuals who linked in the standard ART period were in care and had a viral load of less than 400 copies per mL, compared with 578 (91·6%, 88·1-94·1) of 631 in the rapid ART period (risk ratio 1·01, 95% CI 0·92-1·11). INTERPRETATION: Our findings provide support for the WHO recommendations for rapid ART initiation, and add to the accumulating evidence showing the feasibility, acceptability, and safety of rapid ART initiation in low-income and middle-income country settings. FUNDING: US President's Emergency Plan for AIDS Relief.

OBJECTIVE(S): To determine the proportion of individuals linking to HIV-care with advanced HIV-disease (CD4 ≤200 cells/μL) in the Botswana Combination Prevention Project, describe the characteristics of these individuals, and examine treatment outcomes. DESIGN: A sub-analysis of a cluster-randomized HIV-prevention trial. HIV status was assessed in 16-64-year-olds through home and mobile testing. All HIV-positive persons not on antiretroviral-therapy (ART) were referred to local Ministry of Health and Wellness clinics for treatment. METHODS: Analysis was restricted to the 15 intervention clusters. The proportion of individuals with advanced HIV disease was determined; associations between advanced HIV disease and sex and age explored; and rates of viral suppression determined at 1-year. Mortality and retention in care were compared between CD4 strata (CD4 ≤200 cells/μL vs. > 200 cells/μL). RESULTS: Overall, 17.2% (430/2,499; 95% confidence interval [CI] 15.7-18.8%) of study participants had advanced HIV disease (CD4 ≤200 cells/μL) at time of clinic linkage. Men were significantly more likely to present with CD4 ≤200 cells/μL than women (23.7% versus 13.4%, adjusted odds ratio [aOR] 1.9, 95% CI 1.5-2.3). The risk of advanced HIV disease increased with increasing age (aOR 2.2, 95% CI 1.4-3.2 > 35 years versus < 25 years). Patients with CD4 ≤200 cells/μL had significantly higher rates of attrition from care during follow-up (hazards ratio 1.47, 95% CI 1.1-2.1). CONCLUSIONS: Advanced HIV disease due to late presentation to or disengagement from ART care remains common in the Treat All era in Botswana, calling for innovative testing, linkage, and treatment strategies to engage and retain harder-to-reach populations in care.

Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from </=100 to </=200 cells/microL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101-200 and 6.2% </=100 cells/microL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 </=100 cells/microL and 3.2% (1/31) in CrAg-positive CD4 101-200 cells/microL.

INTRODUCTION: Cryptococcal meningitis remains a significant contributor to AIDS-related mortality despite widened access to antiretroviral therapy. Cryptococcal antigen (CrAg) can be detected in the blood prior to the development of meningitis. The development of highly sensitive and specific rapid diagnostic CrAg tests has helped facilitate the adoption of CrAg screening programs in 19 African countries. AREAS COVERED: The biological rationale for CrAg screening and the programmatic strategies that have been adopted are reviewed. We describe the approach to the investigation of patients with cryptococcal antigenemia and the importance of lumbar puncture to identify individuals who may have cryptococcal meningitis in the absence of symptoms. The limitations of current treatment recommendations and the potential role of newly defined combination antifungal therapies are discussed. A literature review was conducted using a broad database search for cryptococcal antigen screening and related terms in published journal articles dating up to December 2019. Conference abstracts, publicly available guidelines and project descriptions were also incorporated. EXPERT OPINION: As we learn more about the risks of cryptococcal antigenemia, it has become clear that the current management paradigm is inadequate. More intensive investigation and management are required to prevent the development of cryptococcal meningitis and reduce mortality associated with cryptococcal antigenemia.

Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naive adults with advanced HIV/AIDS can reduce the incidence of cryptococcal meningitis (CM) and all-cause mortality. We modeled the cost-effectiveness of laboratory-based "reflex" CrAg screening for ART-naive CrAg-positive patients with CD4<100 cells/microL (those currently targeted in guidelines) and ART-experienced CrAg-positive patients with CD4<100 cells/microL (who make up an increasingly large proportion of individuals with advanced HIV/AIDS). Methods: A decision analytic model was developed to evaluate CrAg screening and treatment based on local CD4 count and CrAg prevalence data, and realistic assumptions regarding programmatic implementation of the CrAg screening intervention. We modeled the number of CrAg tests performed, the number of CrAg positives stratified by prior ART experience, the proportion of patients started on pre-emptive antifungal treatment, and the number of incident CM cases and CM-related deaths. Screening and treatment costs were evaluated, and cost per death or disability-adjusted life year (DALY) averted estimated. Results: We estimated that of 650,000 samples undergoing CD4 testing annually in Botswana, 16,364 would have a CD4<100 cells/microL and receive a CrAg test, with 70% of patients ART-experienced at the time of screening. Under base model assumptions, CrAg screening and pre-emptive treatment restricted to ART-naive patients with a CD4<100 cells/microL prevented 20% (39/196) of CM-related deaths in patients undergoing CD4 testing at a cost of US$2 per DALY averted. Expansion of preemptive treatment to include ART-experienced patients with a CD4<100 cells/microL resulted in 55 additional deaths averted (a total of 48% [94/196]) and was cost-saving compared to no screening. Findings were robust across a range of model assumptions. Conclusions: Reflex laboratory-based CrAg screening for patients with CD4<100 cells/microL is a cost-effective strategy in Botswana, even in the context of a relatively low proportion of advanced HIV/AIDS in the overall HIV-infected population, the majority of whom are ART-experienced.

INTRODUCTION: Non-citizens often face barriers to HIV care and treatment. Quantifying knowledge of positive HIV status and antiretroviral therapy (ART) coverage among non-citizens in a high HIV-prevalence country like Botswana that is close to achieving UNAIDS "90-90-90" targets may expose important gaps in achieving universal HIV testing and treatment. METHODS: The Botswana Combination Prevention Project (BCPP) is a pair-matched cluster-randomized trial evaluating the impact of prevention interventions on HIV incidence in 30 rural or peri-urban communities. Community case finding and HIV testing were conducted in home and mobile venues in 15 intervention communities from October 2013-September 2017. In this secondary analysis, we compared HIV positivity, knowledge of positive HIV-status, and ART status among all citizens and non-citizens assessed at intake in the intervention communities. RESULTS: HIV status was assessed in 57,556 residents in the intervention communities; 4% (n = 2,463) were non-citizens. Five communities accounted for 81% of the total non-citizens assessed. A lower proportion of non-citizens were HIV-positive (15%; n = 369) compared to citizens (21%; n = 11,416) [p = 0.026]; however, a larger proportion of non-citizens did not know their HIV-positive status prior to BCPP testing (75%) as compared to citizens (15%) [p = 0.003]. Among residents with knowledge of their HIV-positive status before BCPP, 79% of the non-citizens (72/91) were on ART compared to 86% (8,267/9,652) of citizens (p = 0.137). CONCLUSIONS: Although non-citizens were less likely to know their HIV-positive status compared to citizens, there were no differences in treatment uptake among non-citizens and citizens who knew their status. Designing interventions for non-citizens that provide HIV testing and treatment services commensurate to that of citizens as well as targeting communities with the largest number of non-citizens may help close a meaningful gap in the HIV care cascade and ensure ethical treatment for all HIV-positive persons. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01965470 (Botswana Combination Prevention Project).

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

Background: High mortality rates among asymptomatic cryptococcal antigen (CrAg)-positive patients identified through CrAg screening, despite preemptive fluconazole treatment, may be due to undiagnosed cryptococcal meningitis. Methods: Symptoms were reviewed in CrAg-positive patients identified by screening 19233 individuals with human immunodeficiency virus infection and CD4 cell counts <100/microL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and at 2 hospitals until June 2016. Cerebrospinal fluid samples from 90 of 254 asymptomatic patients (35%) and 78 of 173 (45%) with headache only were analyzed for cryptococcal meningitis, considered present if Cryptococcus was identified by means of India ink microscopy, culture, or CrAg test. CrAg titers were determined with stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality rate were assessed. Results: Cryptococcal meningitis was confirmed in 34% (95% confidence interval, 25%-43%; 31 of 90) of asymptomatic CrAg-positive patients and 90% (81%-96%; 70 of 78) with headache only. Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (P < .001) and patients with headache only (P = .003). The optimal titer for predicting cryptococcal meningitis was >160 (sensitivity, 88.2%; specificity, 82.1%); the odds ratio for concurrent cryptococcal meningitis was 34.5 (95% confidence interval, 8.3-143.1; P < .001). Conclusions: About a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where it is not possible to perform lumbar punctures in all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis.

Background: Current guidelines recommend screening all people living with human immunodeficiency virus (PLHIV) who have a CD4 count </=100 cells/microL for cryptococcal antigen (CrAg) to identify those patients who could benefit from preemptive fluconazole treatment prior to the onset of meningitis. We conducted a systematic review to assess the prevalence of CrAg positivity at different CD4 cell counts. Methods: We searched 4 databases and abstracts from 3 conferences up to 1 September 2017 for studies reporting prevalence of CrAg positivity according to CD4 cell count strata. Prevalence estimates were pooled using random effects models. Results: Sixty studies met our inclusion criteria. The pooled prevalence of cryptococcal antigenemia was 6.5% (95% confidence interval [CI], 5.7%-7.3%; 54 studies) among patients with CD4 count </=100 cells/microL and 2.0% (95% CI, 1.2%-2.7%; 21 studies) among patients with CD4 count 101-200 cells/microL. Twenty-one studies provided sufficient information to compare CrAg prevalence per strata; overall, 18.6% (95% CI, 15.4%-22.2%) of the CrAg-positive cases identified at </=200 cells/microL (n = 11823) were identified among individuals with a CD4 count 101-200 cells/microL. CrAg prevalence was higher among inpatients (9.8% [95% CI, 4.0%-15.5%]) compared with outpatients (6.3% [95% CI, 5.3%-7.4%]). Conclusions: The findings of this review support current recommendations to screen all PLHIV who have a CD4 count </=100 cells/microL for CrAg and suggest that screening may be considered at CD4 cell count </=200 cells/microL.

UNAIDS 90-90-90 targets and Fast-Track commitments are presented as precursors to ending the AIDS epidemic by 2030, through effecting a 90% reduction in new HIV infections and AIDS-related deaths from 2010 levels (HIV epidemic control). Botswana, a low to middle-income country with the third-highest HIV prevalence, and Australia, a low-prevalence high-income country with an epidemic concentrated among men who have sex with men (MSM), have made significant strides towards achieving the UNAIDS 90-90-90 targets. These two countries provide lessons for different epidemic settings. This paper discusses the lessons that can be drawn from Botswana and Australia with respect to their success in HIV testing, treatment, viral suppression and other HIV prevention strategies for HIV epidemic control. Botswana and Australia are on target to achieving the 90-90-90 targets for HIV epidemic control, made possible by comprehensive HIV testing and treatment programmes in the two countries. As of 2015, 70% of all people assumed to be living with HIV had viral suppression in Botswana and Australia. However, HIV incidence remains above one per cent in the general population in Botswana and in MSM in Australia. The two countries have demonstrated that rapid HIV testing that is accessible and targeted at key and vulnerable populations is required in order to continue identifying new HIV infections. All citizens living with HIV in both countries are eligible for antiretroviral therapy (ART) and viral load monitoring through government-funded programmes. Notwithstanding their success in reducing HIV transmission to date, programmes in both countries must continue to be supported at current levels to maintain epidemic suppression. Scaled HIV testing, linkage to care, universal ART, monitoring patients on treatment over and above strengthened HIV prevention strategies (e.g. male circumcision and pre-exposure prophylaxis) will all continue to require funding. The progress that Botswana and Australia have made towards meeting the 90-90-90 targets is commendable. However, in order to reduce HIV incidence significantly towards 2030, there is a need for sustained HIV testing, linkage to care and high treatment coverage. Botswana and Australia provide useful lessons for developing countries with generalized epidemics and high-income countries with concentrated epidemics.

Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large-scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%–20% of all AIDS-related deaths [1, 2]. Yet cryptococcal meningitis ranks amongst the most poorly funded “neglected” diseases in the world, receiving 0.2% of available relevant research and development (R&D) funding, according to Policy Cures’ 2016 Global Funding of Innovation for Neglected Diseases (G-Finder) Report [3, 4]. | Although cryptococcal meningitis is not formally recognised by the World Health Organisation (WHO) or PLOS Neglected Tropical Diseases (PLOS NTDs) as a neglected tropical disease (NTD), it is listed in the G-Finder report, as it disproportionately affects people in low- and middle-income countries (LMICs), with market failure evident for existing essential antifungal medicines and an urgent need for new, effective, and less toxic medicines. PLOS NTDs defines NTDs as a “group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of LMICs” [5] and according to the WHO, NTDs are “a proxy for poverty and disadvantage”, have “an important impact on morbidity and mortality”, and are relatively “neglected by research” [6]. Although the greatest burden of cryptococcal disease is undoubtedly related to HIV, we demonstrate herein that cryptococcal meningitis meets both the WHO and PLOS NTDs definitions of an NTD, as the disease (1) disproportionately affects populations in poverty and causes substantial morbidity and mortality, (2) primarily affects populations living in tropical and subtropical areas, (3) is immediately amenable to broad control, elimination, or eradication, and (4) is neglected by research [7].

BACKGROUND: Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease. METHODS: We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per muL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/muL not on ART, and those with CD4 less than 100 cells per muL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis. FINDINGS: We estimated an average global cryptococcal antigenaemia prevalence of 6.0% (95% CI 5.8-6.2) among people with a CD4 cell count of less than 100 cells per muL, with 278 000 (95% CI 195 500-340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600-282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600-193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400-234 300), with 135 900 (75%; [95% CI 93 900-163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10-19). INTERPRETATION: Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority.

HIV-associated cryptococcal meningitis (CM) is estimated to cause over half a million deaths annually in Africa. Many of these deaths are preventable. Screening patients for subclinical cryptococcal infection at the time of entry into antiretroviral therapy programs using cryptococcal antigen (CRAG) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with "preemptive" therapy to prevent the development of severe disease. Such CRAG screening programs are currently being implemented in a number of countries; however, a strong evidence base and clear guidance on how to manage patients with subclinical cryptococcal infection identified by screening are lacking. We review the available evidence and propose a treatment algorithm for the management of patients with asymptomatic cryptococcal antigenemia.