Recent advances in managing HIV-associated cryptococcal meningitis

The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis

Adverse drug reactions of Highly Active Antiretroviral Therapy (HAART) in HIV infected patients at the General Hospital, Douala, Cameroon: A cross sectional study

Background: The use of highly active antiretroviral therapy (HAART) as the main option for management of people living with Human Immunedeficiency virus (HIV) is associated with decrease morbidity and mortality. This is due to its effectiveness in inhibiting viral replication. However thiseffectiveness is not without adverse drug effects which in many settings are not monitored. Methods: A cross sectional clinical chart review ofadult Cameroonian patients on HAART between 2003 and 2009 at the Douala General Hospital was done in search of reported HAART-associatedAdverse Drug effects (ADRs). The prevalence of ADR defined as the proportion of the study population with ADR was determined and stratified by age, sex, weight and HAART regimen.Results: Sixty-six (19.5%) of the 339 patients on HAART reported ADRs. Among those who reported ADRs, 29.6% were on D4T-3TC-EFV, 29.3% on D4T-3TC-NVP, 16% on AZT-3TC-EFV and 10.8% on AZT-3TC-NVP. Peripheral Neuropathy was the most common ADR and represented 21.2% of all ADRs. Patients on D4T containing regimens were more likely to develop ADR (OR = 3.5, 95% CI 1.5 –9.8, p<0.01) and 56.1% of all ADRs were associated to D4T. Hospital admissions were for patients with severe anaemia, no fatal cases of ADRs were recorded. Conclusion: HAART-associated ADRs are common and therefore should be actively looked for by caregivers so as to ameliorate the quality of life of HIV patients on treatment.Key words: Adverse drug reaction, HAART, HI

Long term mortality and disability in Cryptococcal Meningitis: a systematic literature review.

Cryptococcal meningitis (CM) is the primary cause of meningitis in HIV-infected adults and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3 months) impact of CM (C. neoformans and C. gattii) on mortality and disability in HIV-infected and non-HIV-infected adults. Though the quality of current evidence is limited, the long-term impact of CM on survival and disability appears to be high. One-year mortality ranged from 13% in an Australian non-HIV C.gattii infected cohort to 78% in a Malawian HIV-infected cohort treated with fluconazole monotherapy. One-year impairment proportions among survivors ranged from 19% in an Australian C.gattii cohort to more than 70% in a Taiwanese non-HIV and HIV-infected cohorts. Ongoing early therapeutic interventions, early detection of impairments and access to rehabilitation services may significantly improve patients' survival and quality of life

Declining trends in vaccine confidence across sub-Saharan Africa: A large-scale cross-sectional modeling study.

Current WHO/UNICEF estimates of routine childhood immunization coverage reveal the largest sustained decline in uptake in three decades with pronounced setbacks across Africa. Although the COVID-19 pandemic has induced significant supply and delivery disruptions, the impact of the pandemic on vaccine confidence is less understood. We here examine trends in vaccine confidence across eight sub-Saharan countries between 2020 and 2022 via a total of 17,187 individual interviews, conducted via a multi-stage probability sampling approach and cross-sectional design and evaluated using Bayesian methods. Multilevel regression combined with poststratification weighting using local demographic information yields national and sub-national estimates of vaccine confidence in 2020 and 2022 as well as its socio-demographic associations. We identify declines in perceptions toward the importance of vaccines for children across all eight countries, with mixed trends in perceptions toward vaccine safety and effectiveness. We find that COVID-19 vaccines are perceived to be less important and safe in 2022 than in 2020 in six of the eight countries, with the only increases in COVID-19 vaccine confidence detected in Ivory Coast. There are substantial declines in vaccine confidence in the Democratic Republic of Congo and South Africa, notably in Eastern Cape, KwaZulu-Natal, Limpopo, and Northern Cape (South Africa) and Bandundu, Maniema, Kasaï-Oriental, Kongo-Central, and Sud-Kivu (DRC). While over 60-year-olds in 2022 have higher vaccine confidence in vaccines generally than younger age groups, we do not detect other individual-level socio-demographic associations with vaccine confidence at the sample sizes studied, including sex, age, education, employment status, and religious affiliation. Understanding the role of the COVID-19 pandemic and associated policies on wider vaccine confidence can inform post-COVID vaccination strategies and help rebuild immunization system resilience

Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL: a systematic review and meta-analysis.

Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg-positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001)

Viral suppression and HIV-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in Malawi: a prospective cohort study.

BACKGROUND Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING Médecins Sans Frontières. TRANSLATIONS For the French and Portuguese translations of the abstract see Supplementary Materials section

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa

Background. Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. Methods. Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. Results. Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC,$1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC,$2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US$208 (95% confidence interval $91–1210) per life-year saved

Cryptococcal antigen in serum and cerebrospinal fluid for detecting cryptococcal meningitis in adults living with HIV: systematic review and meta-analysis of diagnostic test accuracy studies.

Cryptococcal antigen (CrAg) detection could direct timely initiation of antifungal therapy. We searched MEDLINE and EMBASE for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on HIV-positive adults with suspected cryptococcal meningitis (CM). With QUADAS-2, we evaluated risk of bias (RoB) of 11 included studies on 3,600 participants and used random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg was 99.8% (88.4 - 100) and 95.2% (88.7 - 98), respectively; of CSF CrAg was 98.8% (96.2 - 99.6) and 99.3% (96.7 - 99.9), respectively. Agreement between CSF CrAg and CSF culture was 97% (96 - 99). In HIV-adults with CM symptoms, serum CrAg-negativity may rule out CM, positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In first episode of CM, CSF CrAg-positivity is diagnostic

Short-term Mortality Outcomes of HIV-Associated Cryptococcal Meningitis in Antiretroviral Therapy–Naïve and –Experienced Patients in Sub-Saharan Africa

Background: An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for 14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described. / Methods: Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation. / Results: Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6–1.2; P = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8–1.32; P = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART. / Conclusions: In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART

Genetic diversity and microevolution in clinical Cryptococcus isolates from Cameroon.

Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we employ whole genome sequences for 372 clinical Cryptococcus isolates from 341 patients with HIV-associated cryptococcal meningitis obtained via a large clinical trial, across both Malawi and Cameroon, to enable population genetic comparisons of isolates between countries. We see that isolates from Cameroon are highly clonal, when compared to those from Malawi, with differential rates of disruptive variants in genes with roles in DNA binding and energy use. For a subset of patients (22) from Cameroon, we leverage longitudinal sampling, with samples taken at days 7 and 14 post enrolment, to interrogate the genetic changes that arise over the course of infection, and the genetic diversity of isolates within patients. We see disruptive variants arising over the course of infection in several genes, including the phagocytosis regulating transcription factor GAT204. In addition, in 13% of patients sampled longitudinally we see evidence for mixed infections. This approach identifies geographically linked genetic variation, signatures of microevolution, and evidence for mixed infections across a clinical cohort of patients affected by cryptococcal meningitis in Central Africa