Rare and Difficult to Treat Opportunistic Infections- By Arjan Harxhi

The speaker discusses the epidemiology of visceral leishmaniasis (VL). It is caused by Leishmania spp. and manifests in four main forms: cutaneous, mucocutaneous, VL, and post-kala-azar dermal leishmaniasis (PKDL). Each year, over 1 million new leishmaniasis cases and more than 60,000 deaths are reported globally (WHO 2022). In Europe, the epidemiology is complex, involving different Leishmania species and transmission methods. Leishmania infantum is the primary autochthonous species, transmitted by infected female Phlebotomus sandflies, with dogs as the main reservoir. Local transmission of Leishmania tropica occurs in Greece and Leishmania donovani in Cyprus. Over the past 15 years, more than 5,000 VL cases have been reported across 17 European countries. The first human immunodeficiency virus (HIV) and VL co-infection were documented in Spain in 1985, and the concurrent spread of HIV has led to a significant increase in co-infection cases in Europe. 

A review of 34 studies involving over 1,500 individuals with VL-HIV co-infection found a prevalence of around 6%. In Mediterranean countries, this prevalence ranges from 2% to 9%. Co-infection presents challenges due to higher parasite loads, impaired antigen-specific gamma interferon production, lower CD4+ T cell counts, and higher PD1 expression on CD4+ and CD8+ T cells. Clinical presentations vary from mild or asymptomatic to severe, disseminated forms. Most co-infection cases have CD4+ T cell counts < 200, progressing rapidly to advanced disease stages with opportunistic infections. In European AIDS cases, VL is the third most common opportunistic infection. VL is an AIDS-defining condition due to its severe course, high relapse rates, treatment failures, increased drug toxicity, and higher mortality. Post-treatment, one-third of patients relapse within six months and up to 60% within a year, significantly increasing lethality and relapse rates, with a 16% increase in VL lethality when associated with HIV.

The concept of "active chronic VL in HIV patients" was introduced by French authors, indicating that co-infected patients never completely clear the parasites from their blood. This condition includes clinical, oligosymptomatic, and asymptomatic episodes despite therapy, evidenced by consistently positive Polymerase chain reaction (PCR) results and no in vitro resistance to antiparasitic drugs. Parasitological methods are preferred for diagnosis due to their ease and high specificity. Bone marrow aspiration has better sensitivity than classical methods. Serological tests are not recommended for HIV-infected patients due to limited sensitivity; sequential serological testing is suggested for increased sensitivity. Molecular techniques like PCR are highly sensitive and specific, useful for detecting the parasite and monitoring parasite load to predict relapse risk. Microscopic examination demonstrates high sensitivity (93.2%) and specificity (100%) alongside PCR.

Co-infected patients face lower cure rates and higher mortality due to triple failures, toxicity, and relapses, especially with low CD4+ counts. No consensus exists on the optimal drug, dose, duration, or efficacy of combined therapies and maintenance therapy. Combining regimens, notably liposomal amphotericin B (L-AmB) and miltefosine, is suggested due to synergism. Secondary prophylaxis for at least six months is recommended for low CD4+ counts until recovery. EACS guidelines advocate L-AmB (4 mg/kg for 10 days) and its combination with miltefosine. Prophylaxis involves L-AmB every two to four weeks with treatment discontinuation post-recovery or negative PCR or urinary antigen results. Pan-American guidelines recommend L-AmB for treatment and secondary prophylaxis. Additionally, WHO recommends L-AmB plus miltefosine for co-infected patients. 

A survey among HIV-VL co-infected individuals from Central, Eastern, and Southeastern European countries utilized an online questionnaire on epidemiology, diagnosis, and treatment. It aimed to gather comprehensive data on Visceral HIV-VL co-infection in Eastern and Central European countries. Responses from 21 countries and 24 centers were obtained, with limitations including time constraints, data validation, and representativeness. Despite limitations, valuable insights into disease management were obtained. The results indicated an ongoing HIV epidemic for the last 5 years in the European region, with 15 countries reporting over 1000 VL cases in the past decade. Mediterranean countries reported mainly autochthonous VL cases, with primary species being L. infantum, while imported cases were primarily caused by L. donovani. Diagnostic methods favored were microscopy (80%) and PCR (50%), with ELISA being the primary serological diagnostic method. Fewer countries used alternative methods like immunofluorescence and the rK39 test.

The survey found that 60% of respondents have treatment guidelines, especially those reporting co-infections. Eight out of ten have VL treatment guidelines, mainly following EACS and WHO guidelines. Treatment primarily involves L-AmB, sometimes with miltefosine and pentavalent antimonials. Cure assessments rely on clinical judgment and parasitological evaluation in 70% of cases. Over 50% reported relapses and deaths among VL-HIV co-infected patients. One-third use secondary prophylaxis, mainly for CD4+ counts below 200, primarily with L-AmB. Discontinuation criteria include CD4+ count > 350, no relapses, and undetectable viral load. Relapse treatment typically uses L-AmB. In conclusion, there is an urgent need to enhance surveillance and reporting systems for VL and VL-HIV co-infection in ECEE countries and across Europe. Developing unified guidelines and diagnostic algorithms for VL in HIV patients is crucial. Further well-designed clinical research is necessary to generate accurate data on epidemiology, diagnosis, treatment regimens, and prophylaxis of HIV/VL co-infection in the European region. 

Should we Diagnose and Treat Opportunistic Infections Differently in HIV Than in Other Immunocompromised Patients? - By Daria Podlekareva

The speaker provides an overview of opportunistic infections (OIs) in immunocompromised individuals, including those with HIV. The risk factors for OIs and management principles, noting that treatment for specific OIs is similar in both HIV-positive and HIV-negative patients. Immunodeficiency is classified as primary or congenital and secondary or acquired, with secondary mainly due to iatrogenic immunosuppression from medical treatment like transplants, cytotoxic drugs, immunomodulators, and corticosteroids. OIs arise from normally harmless pathogens, becoming pathogenic when the body's defence is compromised, either by reactivation, transmission, or severe infection. AIDS in HIV patients is defined by a CD4+ cell count <200 cells/mm3 or an AIDS-defining illness, indicating advanced immune suppression. Understanding the type of immune deficiency is crucial for managing infections, with different cell line defects resulting in various infections. HIV primarily affects CD4 T cells, and certain patient categories are more susceptible to OIs, including organ transplant recipients, hematological malignancy patients, and those on chemotherapy. An HIV infection progresses naturally, with initial latency followed by viral replication leading to a rapid decline in CD4 cell count and increased risk of OIs. Specific CD4 cell cutoffs are established for certain OIs, with prophylaxis recommended below these thresholds.

The introduction of antiretroviral therapy (ART) in the late nineties drastically reduced the incidence of AIDS and mortality in HIV patients. However, despite these improvements, OIs remain a concern, particularly among late presenters with low CD4 cell counts. In Europe, over 50% of newly diagnosed HIV cases are late presenters, a trend that has remained stable over the past decade. Late presenters, individuals with poor retention in care, and those not on stable ART are at increased risk of OIs. As life expectancy increases for HIV patients, they may develop other immunocompromised conditions like malignancies and autoimmune diseases. Pneumocystis jirovecii pneumonia (PCP) is a common OI, with higher incidence rates in non-HIV immunocompromised populations but better survival rates among HIV patients due to routine prophylaxis and younger age. Studies comparing PCP patients with and without HIV show significantly better survival rates among HIV-positive individuals.

Cryptococcal meningitis is a significant issue in resource-limited countries with high HIV prevalence, notably in sub-Saharan Africa, where it surpasses tuberculosis as a leading cause of death among HIV patients. Invasive cryptococcal disease occurs in 1,700-6,600 cases per 100,000 HIV patients annually. It also affects cancer patients, especially those with lymphoma and chronic leukemia, and up to 2% of liver transplant recipients. Symptoms include fever, altered mental status, and headaches, with lower inflammation in HIV patients. A study of 207 patients (1996-2009) showed a decline in severe cryptococcal disease among HIV-positive patients and an increase among HIV-negative cases. HIV-positive patients often had cryptococcal meningitis, while transplant recipients commonly had pulmonary disease.

Prior to ART, cytomegalovirus (CMV) infection rates in HIV patients were about 12 cases per 100 person-years, with CMV retinitis at 7.55 cases per 100 person-years. Cancer patients, especially with multiple myeloma, had incidences of 2.2 to 18 per 1,000 patients. CMV affects up to 40% of solid organ and 75% of bone marrow transplant recipients without prophylaxis, often causing graft rejection. HIV patients mainly suffer from CMV retinitis, while transplant patients show pneumonitis and gastrointestinal issues. Relapses are common in HIV patients, with high mortality and graft rejection rates in transplant patients. Prophylactic guidelines exist for transplant patients but not for HIV patients.

TB is the leading opportunistic infection globally, especially affecting immunocompromised patients like those with HIV. TB can arise from recent transmission or latent TB reactivation. Untreated HIV patients with latent TB face up to a 15% annual reactivation risk. Clinical presentation varies with CD4 counts: higher counts show pulmonary TB, while counts < 200 often present atypical, extrapulmonary, and disseminated TB. The patient origin and immune status influence TB development. Testing for latent TB using interferon-ϒ release assays or tuberculin skin tests is essential, followed by ruling out active TB and treating latent infections. Immediate prophylaxis is recommended after significant exposure. Managing TB in HIV patients involves considering ART timing, drug interactions, toxicities, immune reconstitution syndrome, and drug resistance. ART typically starts within two weeks of TB treatment, except for TB or cryptococcal meningitis, where a four-week delay is advised. 

Immune reconstitution inflammatory syndrome (IRIS) is crucial in managing OIs in HIV patients. Effective ART reduces viral load, boosting immune function, which can trigger inflammatory responses to dormant antigens. IRIS has two types: "unmasking," where latent conditions become symptomatic, and "paradoxical," where known conditions worsen. It usually occurs within three months of starting ART and is common with CMV, TB, and cryptococcal infections. EACS guidelines recommend prednisolone for TB-related IRIS and deferring ART for cryptococcal meningitis. Preventing OIs involves ART adherence, prophylaxis, and early HIV diagnosis and treatment. Managing secondary immune deficiency focuses on improving the primary condition with ART and antibiotic prophylaxis for OIs. 

Prophylaxis of Opportunistic Infections-By Anton Pozniak

ART stands as the cornerstone of prophylaxis for HIV patients, significantly reducing the risk of OIs. The efficacy of ART has evolved drastically since its introduction in the mid-1990s, with triple therapy proving highly effective. Data from the late '90s to the early 2000s illustrate a sharp decline in OIs, marking a pivotal shift in HIV management. While global data on OIs has declined in recent years, the cost-effectiveness of ART remains staggering, with substantial reductions in OI risk and associated cost savings. Notably, ART has been particularly impactful in preventing OIs like oral candidiasis, cerebral toxoplasmosis, and PCP. In low and middle-income countries, where ART costs are lower, its preventive benefits are profound. In the ART era, common OIs to consider for prophylaxis include candidiasis, TB, Herpes zoster, and bacterial pneumonia, with similar trends observed globally across different regions.

The primary prophylaxis is aimed at preventing the first disease episode and is guided by CD4 count. Secondary prophylaxis focuses on preventing disease relapse post-treatment. Various regimens, including co-trimoxazole, were utilized for PCP prophylaxis based on CD4 count thresholds. Additionally, alternative prophylactic agents like Tovacoin emerged. Toxoplasma and PCP can be simultaneously prevented with co-trimoxazole. Notably, primary prophylaxis for Mycobacterium avium complex (MAC) has shifted due to the effectiveness of ART. Immediate ART initiation at CD4 counts <50 obviates the need for MAC chemoprophylaxis, provided active disease is excluded. This change reflects ART's role in bolstering immunity against latent MAC infections, potentially reducing MAC-related mortality.

According to WHO, Co-trimoxazole prophylaxis is recommended for all severely immunosuppressed individuals and children aged < 5 years, regardless of CD4 count. In HIV and TB co-infections, Co-trimoxazole is recommended regardless of CD4 count. Notably, in low and middle-income countries with endemic malaria and bacterial infections, Co-trimoxazole is also recommended due to observed reductions in these infections. In pregnant patients, a unique consideration is that Trimethoprim-sulfamethoxazole is recommended for PCP prophylaxis after the first trimester. However, guidance is lacking for pregnant individuals with HIV presenting in the first trimester, leaving the decision to individual patient discussion. In terms of discontinuation, recent recommendations suggest stopping PCP prophylaxis if the CD4 count rises above 100 and remains undetectable after three months of ART therapy, reflecting the impact of viral suppression on prophylactic needs. Similar considerations apply to Toxoplasma prophylaxis, while MAC prophylaxis can be ceased upon initiating ART therapy.

There's limited evidence supporting prophylaxis initiation against certain organisms like Candida spp, Cryptosporidium, CMV, and Bartonella spp. The impact of prophylaxis on public health or individual outcomes remains uncertain due to a lack of substantial studies. However, prophylaxis may be considered for specific infections in individual cases. For example, fluconazole prophylaxis for Coccidioidomycosis may be administered if the CD4 count is <250 cells/μL, especially in regions like Arizona or parts of California. The preemptive therapy is provided for asymptomatic Cryptococcus patients who are antigen-positive, similar to latent TB management. Secondary prophylaxis, aimed at preventing disease recurrence, often revolves around a CD4 count threshold of 200. For instance, MAC treatment typically lasts a year, with cessation considered when the CD4 count rises and the patient remains asymptomatic. Cryptococcal therapy discontinuation is suggested after a year if the CD4 count is 100 and the viral load is undetectable. However, guidance for halting histoplasmosis prophylaxis is not understood, and CMV prophylaxis depends on CD4 count.

Understanding the risks associated with drug prophylaxis is crucial. Nowadays, first-line ARTs have minimal side effects, reducing overlaps with prophylaxis-related adverse effects. Attention must be given to adverse drug reactions and drug interactions, particularly in patients on chemotherapy or HIV therapy. Complex regimens pose challenges, especially for newly diagnosed HIV patients. Managing risks during this crucial period is vital, particularly for those presenting late. Websites like the Liverpool database offer resources for checking drug interactions, which is essential even for experienced clinicians. Despite advancements, minimizing risks remains crucial, extending beyond serious illnesses to include various preventative measures for asymptomatic patients. This broader approach encompasses immunity against hepatitis A and B, addressing epidemics like syphilis and bacterial infections, environmental factors like global warming, risks associated with animals and pets, and ensuring food and water safety, especially during travel for immunocompromised individuals.

Vaccines are essential in effective prophylaxis, particularly in patients with low CD4 counts, aiming for durable protection. The strategy often involves administering ART to elevate CD4 levels before vaccination, ensuring optimal immune response. Inactivated vaccines are preferred over live ones, with efficacy influenced by CD4 counts, which are less of a concern once the count exceeds 200 cells/μL. Revaccination may be necessary if doubts persist about vaccine efficacy. Notably, pneumococcal and seasonal flu vaccines are underutilized in many regions despite their importance. Additionally, the zoster vaccine is recommended, particularly for HIV patients with age > 60, with efforts to expand eligibility to younger age groups. Prophylaxis remains crucial due to undiagnosed or late HIV diagnoses and treatment interruptions. While ARVs have significantly reduced OIs, the risk persists, especially in the first year of treatment. Thus, vaccines play a continuing role in minimizing risks alongside antimicrobials.

Opportunistic Infections in the ART Era: Barriers to Optimal Management -By Cristiana Oprea

The epidemiology of OIs in people living with HIV has seen significant developments in Europe, particularly in Eastern and Central Europe. At the Victor Babes Hospital in Bucharest, Romania, extensive research and treatment efforts have been documented. Historically, there was a severe pediatric HIV cohort in the late 1980s due to parenteral transmission, with many children experiencing severe OIs. Notable cases include children with molluscum contagiosum lesions, Kaposi sarcoma, extensive brain infections such as toxoplasmosis with multiple abscesses, primary cerebral lymphoma, progressive multifocal leukoencephalopathy, and rare infections like focal CMV encephalitis and cryptococcosis. These conditions presented with severe symptoms, including significant brain edema, demyelination, and gelatinous pseudocysts in the brain. The survey findings highlighted the critical need for better diagnostic tools and treatment access to manage OIs effectively in Central and Eastern Europe. 

Despite ART advancements, OIs persist, especially in Central Asia and Eastern Europe, with a 48% increase in HIV infections and a 32% rise in AIDS-related deaths since 2010. UNAIDS reports only 41% of men and 61% of women achieve viral suppression in this region, attributing challenges to late HIV diagnosis, poor ART adherence, and inadequate prophylaxis for low CD4 counts. A study involving over 20,000 people infected with HIV (PLWH) and 1,600 AIDS-defining illnesses underscores significant regional disparities, with Eastern Europe reporting over 590 cases, primarily oesophagal candidiasis and TB. Although OI rates have decreased since 2017, they remain disproportionately high in Eastern Europe and Central Asia compared to other European regions, with a notable increase in malignancies like non-Hodgkin lymphoma in recent years. Low CD4 counts of < 100, belonging to key populations like drug users, and subpar ART contribute to increased AIDS-related illnesses. Targeted interventions are vital for improving early diagnosis, ART adherence, and prophylactic access, especially in high-risk groups and areas with limited HIV care infrastructure.

Globally, TB poses a significant threat to PLWH, particularly in Eastern Europe (EE) and Central Asia, where multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) rates are high. Limited access to drug susceptibility testing (DST) in EE leads to delayed and inappropriate treatment, with over 64% of cases experiencing delayed diagnosis. A study in Romania revealed alarming rates of TB co-infection among PLWH who inject drugs, with 70% of cases being multidrug-resistant. Improving TB management in high-burden regions is crucial, necessitating enhanced access to DST, timely screening, and appropriate treatment to mitigate the impact of TB on PLWH, especially vulnerable populations.

Cryptococcal infections present a significant global health challenge, with EE and Central Asia bearing notable burdens. While the incidence is higher than in Western Europe but lower than in African countries, cryptococcal infections account for approximately 90% of AIDS-related deaths in the region. Out of 4.3 million individuals with advanced HIV disease globally, around 179,000 are affected by cryptococcal infection, resulting in 112,000 deaths, emphasizing the need for improved prevention, diagnosis, and treatment efforts. A 15-year study in EE focused on brain OIs among PLWH, revealing concerning trends. Progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, TB meningitis, cryptococcal meningitis, and primary cerebral lymphoma with CMV encephalitis were prevalent. CD4 cell counts were alarmingly low, particularly in cases of CMV encephalitis and cryptococcal meningitis, indicating severe immunosuppression and heightened vulnerability to OIs. Between 2014 and 2023, "Victor Babes" Hospital in Bucharest diagnosed 813 PLWH with opportunistic infections (OIs), with tuberculosis (TB) being the most common, accounting for 494 cases. This underscores the ongoing challenge of OIs in Central and Eastern Europe, with TB prevailing. Additionally, cases of progressive multifocal leukoencephalopathy (PML), esophageal candidiasis, Pneumocystis pneumonia (PCP), and cerebral toxoplasmosis were identified.

A survey was conducted across Central and EE countries to identify persistent barriers in diagnostic and treatment procedures for prevalent OIs, prompting a comparative analysis between EU and non-EU nations. The questionnaire, comprising 35 questions, was distributed to senior HIV physicians from 25 countries. Analysis revealed a substantial number of newly diagnosed cases in 2023, notably in Ukraine, Russia, Belarus, and Poland, with the latter experiencing an increase due to migration triggered by the Ukraine war. Several smaller countries also reported significant cases. The percentage of late presenters, those diagnosed with a CD4 count < 350, remains high across many countries, with rates exceeding 50% in some. Variations in diagnosed OIs were observed between EU and non-EU countries, with TB and PCP more prevalent in the non-EU countries. Access to HIV healthcare varied, with some countries requiring health insurance for treatment. However, countries like Romania cover patients under the national HIV program, ensuring access to treatment and monitoring.

Additionally, survey results revealed that there remains a medium to high level of medical stigma in both EU and non-EU countries with low access to sexual health clinics. In particular, EU nations lack mental health oversight and integrated medical care. Social support appears relatively consistent across both country categories, yet national guidelines for treating OIs are more frequently utilized in non-EU countries than in EU countries. Access to bronchoscopy, non-tuberculosis mycobacteria PCR, and multiplex respiratory PCR is notably lower in non-EU countries. Similarly, access to diagnostic methods for brain OIs, such as PCR multiplexing, cerebrospinal fluid analysis, brain MRI, and cryptococcal antigen testing, as well as brain biopsy, is considerably lower in non-EU countries. Specific diagnostic methods for suspected brain OIs, including PCR for cytomegalovirus, toxoplasma, and JC virus, are also less accessible in non-EU countries compared to their EU counterparts. Similar disparities in recommended treatments exist, with notable shortages in injectable Methotrexate, Toxazole, Sulphadiazine, Pyrimethamine, and Flucytosine in non-EU countries. Access to medications like delamanid and bedaquiline is limited in both EU and non-EU countries. a. However, in countries with low tuberculosis burdens, the need for such treatments for multidrug-resistant tuberculosis (MBRTB) may be minimal. Access to specific drugs such as Delamanid and Bedaquiline remains limited across both EU and non-EU countries.

Therefore, various barriers to optimal management of OIs persist, including war-related stress, migration, lack of access to specific treatments and modern diagnostic methods, lack of integrated care, substance use, insufficient resources for harm reduction, reduced access to sexual health clinics and stigmatization. In summary, OIs continue to pose challenges in the European region despite advancements in HIV treatment, with significant differences and inequalities persisting in access to modern diagnostics and treatment coverage.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024, 27th April–30th April 2024, Barcelona, Spain