Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

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.

Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial.

BACKGROUND: Despite satisfactory efficacy of WHO-recommended second-line antiretroviral treatment for patients with HIV in low-income countries, the need for simplified, low-cost, and less-toxic maintenance strategies remains high. We compared boosted protease inhibitor monotherapy with dual therapy with boosted protease inhibitor plus lamivudine in patients on second-line antiretrovial therapy (ART). METHODS: We did a multicentre, randomised, parallel, open-label, superiority, trial in the HIV services of five hospitals in sub-Saharan Africa (Yaoundé, Cameroon; Dakar, Senegal; and Bobo Dioulasso, Burkina Faso). We recruited patients from the long-term, post-trial cohort of the ANRS 12169/2LADY study that compared the efficacy of three second-line combinations based on boosted protease inhibitors. Participants for our study were HIV-1 infected with multiple mutations including M184V, at first-line failure, aged 18 years and older, on boosted protease inhibitor plus two nucleoside reverse transcriptase inhibitors (NRTI) for at least 48 weeks with at least 48 weeks follow-up in the 2LADY trial, with two viral load measurements of less than 200 copies per mL in the previous 6 months, CD4 counts of more than 100 cells per µL, adherence of at least 90%, and no change to ART in the past 3 months. We randomly assigned participants (1:1) to receive either monotherapy with their boosted protease inhibitor (once-daily darunavir 800 mg [two 400 mg tablets] boosted with ritonavir 100 mg [one tablet] or coformulation of lopinavir 200 mg with ritonavir 50 mg [two tablets taken twice per day]) or to boosted protease inhibitor plus once-daily lamivudine 300 mg (one 300 mg tablet or two 150 mg tablets). Computer-generated randomisation was stratified by study site and viral load at screening (< 50 copies per mL, and 50-200 copies per mL), and concealed from study personnel throughout the inclusion period. After randomisation, treatment allocation was not masked from clinicians or patients]. Patients had follow-up visits at weeks 4 and 12, and every 3 months until 96 weeks; if viral load exceeded 500 copies per mL at any visit, NRTI (tenofovir and lamivudine) were reintroduced into treatment. The primary outcome was the proportion of participants who had treatment failure at 96 weeks in the intention-to-treat analysis, where treatment failure was defined as one of the following: a confirmed viral load of more than 500 copies per mL, reintroduction of NRTI, or interruption of boosted protease inhibitor. We designed the study to detect a difference of 12% between groups in the primary outcome, with an expected 20% of patients having treatment failure in the monotherapy group. This study is registered with ClinicalTrials.gov, number NCT01905059. FINDINGS: Between March 5, 2014, and Jan 26, 2015, 265 participants were assigned to receive monotherapy (133) or boosted protease inhibitor plus lamivudine (132). At week 48, an independent data safety monitoring board reviewed data, and advised discontinuation of the monotherapy group because the number of failures had exceeded the expected 20%; therefore results here are for week 48. At this point, treatment failure occurred in four (3·0%; 95% CI 0·8-7·6) of 132 participants on dual therapy and 33 (24·8%; 17·7-33·0) of 133 participants on monotherapy (relative risk 8·2, 95% CI 3·0-22·5; odds ratio 10·6, 95% CI 3·6-42·1). The difference between groups (21·8%, 95% CI 13·9-29·7; p<0·0001) showed superiority of dual therapy compared with monotherapy. We recorded 46 severe adverse events of grade 3 or 4 (29 in the monotherapy group, 17 in the boosted protease inhibitor plus lamivudine group); one event in the montherapy group (intoxication resulting from co-administration of ritonavir-boosted lopinavir with an ergotamine derivate) was deemed related to study drug. Two participants in the monotherapy group and one in the dual therapy group died, all from causes not related to study drugs or procedures (one from complications from gastric cancer surgery, one in a work accident, and one from a lung disease of unknown cause). INTERPRETATION: After viral suppression with boosted protease inhibitor plus NRTI in second-line ART, maintenance therapy with boosted protease inhibitor plus lamivudine was associated with a high rate of success, despite the presence of M184V mutations at first-line treatment failure. Results indicated that boosted protease inhibitor monotherapy cannot be recommended for these patients. FUNDING: Agence National de Recherche sur le Sida et les hépatites and Janssen Pharmaceutica.

Ending AIDS as a public health threat by 2030: Scientific Developments from the 2016 INTEREST Conference in Yaoundé, Cameroon.

The underpinning theme of the 2016 INTEREST Conference held in Yaoundé, Cameroon, 3-6 May 2016 was ending AIDS as a public health threat by 2030. Focused primarily on HIV treatment, pathogenesis and prevention research in resource-limited settings, the conference attracted 369 active delegates from 34 countries, of which 22 were in Africa. Presentations on treatment optimization, acquired drug resistance, care of children and adolescents, laboratory monitoring and diagnostics, implementation challenges, HIV prevention, key populations, vaccine and cure, hepatitis C, mHealth, financing the HIV response and emerging pathogens, were accompanied by oral, mini-oral and poster presentations. Spirited plenary debates on the UNAIDS 90-90-90 treatment cascade goal and on antiretroviral pre-exposure prophylaxis took place. Joep Lange career guidance sessions and grantspersonship sessions attracted early career researchers. At the closing ceremony, the Yaoundé Declaration called on African governments; UNAIDS; development, bilateral, and multilateral partners; and civil society to adopt urgent and sustained approaches to end HIV by 2030.

Cross-sectional assessment of three commonly used measures of adherence to combination antiviral therapy in a resource limited setting.

Nowadays, global coverage of combination antiretroviral therapy (cART) has increased due to a continuous process to scale up access. This increase has potentially transformed HIV-infection from a fatal to a chronic disease: a transformation only possible if the prescribed medications are taken accordingly. We therefore evaluated optimal adherence to cART by three commonly used methods: visual analogue scale (VAS), four days recall (FDR) and clinic attendance (CA) for the last six months in 301 HIV-infected patients on cART for at least six months at the Douala General Hospital, Cameroon. Optimal adherence was defined to be greater than or equal to the 95th percentile estimate of each method. We found that 70.8% of our study population was female. The mean age was 40.8 years (SD 10.5) and 85% were on first line cART. Median CD4 count was 397 cells/ml (252-559). Optimal adherence by VAS, FDR and CA, was 68.1%, 83.4%, and 73.4%, respectively. VAS and FDR inter-correlated strongly (Pearson's Chi square coefficient, r = 0.58, p < 0.001). Higher CD4 count above 200 cells/ml was associated with optimal adherence by CA (Adjusted Odds Ratio [AOR]:2.6 (95% CI: 1.2-5.3, p < 0.001)). As high optimal adherence to cART is associated with good clinical outcome in HIV patients, simple methods such as the VAS for evaluating adherence, should be integrated to the HIV clinic of the Douala General Hospital.

New indicators for delay in initiation of antiretroviral treatment: estimates for Cameroon.

OBJECTIVE: To propose two new indicators for monitoring access to antiretroviral treatment (ART) for human immunodeficiency virus (HIV); (i) the time from HIV seroconversion to ART initiation, and (ii) the time from ART eligibility to initiation, referred to as delay in ART initiation. To estimate values of these indicators in Cameroon. METHODS: We used linear regression to model the natural decline in CD4+ T-lymphocyte (CD4+ cell) numbers in HIV-infected individuals over time. The model was fitted using data from a cohort of 351 people in Côte d'Ivoire. We used the model to estimate the time from seroconversion to ART initiation and the delay in ART initiation in a representative sample of 4154 HIV-infected people who started ART in Cameroon between 2007 and 2010. FINDINGS: In Cameroon, the median CD4+ cell counts at ART initiation increased from 140 cells/µl (interquartile range, IQR: 66 to 210) in 2007-2009 to 163 cells/µl (IQR: 73 to 260) in 2010. The estimated average time from seroconversion to ART initiation decreased from 10.4 years (95% confidence interval, CI: 10.3 to 10.5) to 9.8 years (95% CI: 9.6 to 10.0). Delay in ART initiation increased from 3.4 years (95% CI: 3.1 to 3.7) to 5.8 years (95% CI: 5.6 to 6.2). CONCLUSION: The estimated time to initiate ART and the delay in ART initiation indicate that progress in Cameroon is insufficient. These indicators should help monitor whether public health interventions to accelerate ART initiation are successful.

A randomized blinded controlled trial of mobile phone reminders on the follow-up medical care of HIV-exposed and HIV-infected children in Cameroon: study protocol (MORE CARE).

BACKGROUND: In Cameroon, only two-thirds of children with HIV exposure or infection receive appropriate HIV-directed medical care. Mortality, antiretroviral therapy resistance and suboptimal virological response are strongly related to missed opportunities for treatment, and, more specifically, to skipped scheduled medical appointments. The present trial, MORE CARE (Mobile Reminders for Cameroonian Children Requiring HIV Care) seeks to determine if reminders sent by text message (SMS), phone call, or concomitant SMS and phone calls most increase the presence at medical appointments of HIV-infected or -exposed children (efficacy), and which is the most efficient related to working time and financial cost (efficiency). METHODS/DESIGN: We will carry out a multicenter single-blind, randomized, factorial controlled trial. A randomization list will be electronically generated using random block sizes. Central allocation will be determined by sequentially numbered. A total of 224 subjects will be randomized into four groups (SMS, Call, SMS + Call, and Control) with an allocation ratio of 1:1:1:1. SMS and calls will be sent between 48 and 72 hours before the scheduled appointment. A medical assistant will send out text messages and will call participants. Our primary outcome is appointment measured by efficacy and efficiency of interventions. We hypothesize that two reminders (concomitant use of SMS and phone calls) as an appointment reminder is more effective to improve appointment compared to one reminder (only SMS or only call), and that the most efficient is use of only SMS. The analysis will be intention to treat. DISCUSSION: This trial investigates the potential of SMS and phone calls as motivational reminders to improve children's adherence to medical appointments for HIV-related care in Cameroon. The intervention will act to end missed appointment due to forgetfulness. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR201304000528276.

Monitoring of HIV viral load, CD4 cell count, and clinical assessment versus clinical monitoring alone for antiretroviral therapy in low-resource settings (Stratall ANRS 12110/ESTHER): a cost-effectiveness analysis.

BACKGROUND: In low-income countries, the use of laboratory monitoring of patients taking antiretroviral therapy (ART) remains controversial in view of persistent resource constraints. The Stratall trial did not show that clinical monitoring alone was non-inferior to laboratory and clinical monitoring in terms of immunological recovery. We aimed to evaluate the costs and cost-effectiveness of the ART monitoring approaches assessed in the Stratall trial. METHODS: The randomised, controlled, non-inferiority Stratall trial was done in a decentralised setting in Cameroon. Between May 23, 2006, and Jan 31, 2008, ART-naive adults were randomly assigned (1:1) to clinical monitoring (CLIN) or viral load and CD4 cell count plus clinical monitoring (LAB) and followed up for 24 months. We calculated costs, number of life-years saved (LYS), and incremental cost-effectiveness ratios (ICERs) with data from patients who had been followed up for at least 6 months. We considered two cost scenarios in which viral load plus CD4 cell count tests cost either US$95 (scenario 1; Abbott RealTime HIV-1 assay) or $63 (scenario 2; generic assay). We compared ICERs with a WHO-recommended threshold of three times the per-person gross domestic product (GDP) for Cameroon ($3670-3800) and an alternative lower threshold of $2385 to determine cost-effectiveness. We assessed uncertainty with one-way sensitivity analyses and cost-effectiveness acceptability curves. FINDINGS: 188 participants who underwent LAB and 197 who underwent CLIN were followed up for at least 6 months. In scenario 1, LAB increased costs by a mean of $489 (SD 430) per patient and saved 0·103 life-years compared with CLIN (ICER of $4768 [95% CI 3926-5613] per LYS). In scenario 2, the incremental mean cost of LAB was $343 (SD 425) -ie, an ICER of $3339 (2507-4173) per LYS. A combined strategy in which LAB would only be used in patients starting ART with a CD4 count of 200 cells per µL or fewer suggests that 0·120 life-years would be saved at an additional cost of $259 per patient in scenario 1 (ICER of $2167 [95% CI 1314-3020] per LYS) and $181 in scenario 2 (ICER of $1510 [692-2329] per LYS) when compared with CLIN. INTERPRETATION: Laboratory monitoring was not cost effective in 2006-10 compared with clinical monitoring when the Abbott RealTime HIV-1 assay was used according to the $3670 cost-effectiveness threshold (three times per-person GDP in Cameroon), but it might be cost effective if a generic in-house assay is used. FUNDING: French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Ensemble pour une Solidarité Thérapeutique Hospitalière En Réseau (ESTHER).

Decentralization of access to antiretroviral therapy in Cameroon: correlates of HIV physicians' knowledge in HIV care.

BACKGROUND: Good knowledge in HIV care among physicians is a necessary prerequisite to effective antiretroviral therapy (ART) scaling-up in Sub-Saharan Africa. METHODS: Between September 2006 and March 2007, a 27-item knowledge questionnaire was proposed to all HIV physicians working in 27 hospitals throughout six provinces of Cameroon. Physicians' responses were compared between the three levels of decentralization of the Cameroonian healthcare delivery system (χ(2) and Fisher tests). Correct responses were summed to build a knowledge score. Factors significantly associated with a higher score were identified using linear regression. RESULTS: In total, 93 physicians filled in the questionnaire. Level of knowledge was globally good (median score 23), with no significant difference between the three levels of decentralization. Gaps in knowledge were observed regarding the use of cotrimoxazole and the follow-up of ART-treated patients. Main factors independently associated with a higher knowledge score included training, involvement in therapeutic committees, satisfactory collaboration with other practitioners and establishment of strong relationships between patients and patients' associations. CONCLUSIONS: Overall knowledge in HIV care is good among HIV physicians working at all three levels of decentralization of healthcare in Cameroon. However, a national training policy should be set up to improve knowledge and practices in both ART follow-up and specific situations such as paediatric HIV. Collaboration between caregivers and external resources involved in HIV care should also be encouraged.

Implementing operational research to scale-up access to antiretroviral therapy for HIV infection: lessons learned from the Cameroonian experience.

PURPOSE OF REVIEW: Given the lack of evidence on how to best design and implement antiretroviral therapy (ART) scaling-up policies, operational research has seen a surge in interest. There is, however, little published information on the contribution of operational research in ART programs' implementation or in improvement of associated outcomes. The article focuses therefore on how operational research may contribute to such improvements and what the key enabling factors are for its integration into program frameworks. RECENT FINDINGS: One of the most systematic operational research linked to a national ART program on the African continent was conducted in Cameroon between 2006 and 2010. Along with operational research carried out elsewhere in Africa, it helped demonstrate that a strategy of decentralizing HIV care can increase treatment coverage and improve early access to care, while maintaining good clinical outcomes. Multipartnership between local researchers, national authorities, healthcare professionals and the civil society is the key enabling factor for the relevance of operational research and the translation of its results into policy and practice. SUMMARY: In spite of a dramatic increase in access to ART during recent years in low-income countries, the fight against HIV remains a failure in terms of the goal of breaking the pandemic dynamic. Operational research is needed more than ever to face this challenge.

Scaling up access to antiretroviral treatment for HIV infection: the impact of decentralization of healthcare delivery in Cameroon.

BACKGROUND: The independent evaluation of the Cameroonian antiretroviral therapy (ART) Programme, which reached one of the highest coverage in the eligible HIV-infected population (58%) in Sub-Saharan Africa, offered the opportunity to assess ART outcomes in the context of the decentralization of HIV care delivery. MATERIALS AND METHODS: A cross-sectional survey (EVAL, ANRS 12-116, 2007) was carried out in a random sample of 3151 HIV-positive patients (response rate 90%) attending 27 treatment centres at the different level of the healthcare delivery (central, provincial and district), as well as in the exhaustive sample of doctors in charge of HIV care in these centres (response rate 92%, n = 97). Multivariate two-level analyses were conducted to assess the impact of the level of healthcare delivery on CD4 cell gains since initiation of treatment and adherence to treatment in the subsample of patients who were ART-treated for 6 months or more (n = 1985). RESULTS: District treatment centres were characterized by more limited technical and human resources but a lower workload. ART-treated patients followed up in these centres had significantly lower socioeconomic status. After adjustment for other explanatory factors, immunological improvement was similar in patients followed up at the central and district level, whereas adherence to ART was better both at provincial and district levels. CONCLUSION: Success in scaling-up access to ART in Cameroon has been facilitated by decentralization of the healthcare system. Long-term sustainability urgently implies better integration of this HIV-targeted programme in the global healthcare reform of financing mechanisms, management of human resources and drug procurement systems.