Pattern of HIV-related central nervous system disorders varies by region, evolving alongside access to antiretroviral therapy

Limited data on the incidence of CNS disorders in many settings

Opportunistic infections of the CNS, such as cerebral toxoplasmosis, Cryptococcal meningitis (CM) and progressive multifocal leukoencephalopathy (PML) and other brain disorders caused directly by HIV infection (such as HIV dementia) are among the most serious complications that can afflict people with HIV.

Although the incidence of such problems has decreased dramatically in the industrialised world since the introduction of ART, the overall global burden of these complications is believed to be growing along with the increasing number of people infected with HIV in resource limited settings — the vast majority of whom continue to be without access to optimal treatment and care.

Yet, the actual prevalence HIV-related neurological disease in many parts of the world is still being delineated. “There is a paucity of data,” Professor James Hakim of the University of Zimbabwe told colleagues, because most developing world settings have a limited capacity to diagnose CNS disorders. There are usually few, if any, neurologists, poor access to imaging equipment, and limited laboratory capabilities to do microbiology, histology, etc, needed to confirm diagnoses.

In addition, Prof. Hakim noted that in many places, before the availability of ART, there simply wasn’t much reason to look for something that couldn’t be treated.

But with increasing access to ART that now seems to be changing. Indeed, during one presentation, Dr Darma Imran of the University of Indonesia reported that there was a steep increase in the number of cases of toxoplasmosis diagnosed in Jakarta from 2004 to 2006, at approximately the same time ART was introduced into the public health system in Indonesia. So paradoxically, when reported rates of conditions in some countries look like they are increasing, this could simply be a reflection of improved access to care.

The reported frequency of the various central nervous system (CNS) complications associated with HIV infection differs from region to region, and according to some of the world’s leading experts who gathered recently in Venice to discuss HIV-related brain disorders, the patterns also appear to be evolving — in sometimes unexpected ways — with increasing access to antiretroviral therapy (ART) and care.

The neurologists and other experts, gathered from April 14-16^th for two sequential meetings, the Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings, followed immediately by a meeting on the Evolving Mechanisms of HIV Neuropathogenesis in the HAART Era: Domestic and Global Issues.

This article, the first in an exclusive series of aidsmap.com reports on the meetings, will focus primarily on the global epidemiology of HIV-associated CNS disease, with a focus on resource-limited settings.

Geographical variations in the patterns of CNS disease

Dr Giovanni Rezza of the Instituto Superiore di Sanità in Rome cautioned the audience not to rush into premature conclusions about differences in the risks of conditions among different populations, because of differences in methods of analysis used from one study to another, and because of obvious differences in access to care and diagnostic capacity which bias which events get reported.

Nevertheless, in the various reports presented during the first morning of the conference, there do appear to be some differences in the patterns of CNS diseases (both before and after ART) seen from one region to another.

“In Sub-Saharan Africa, the commonest described HIV-associated CNS illnesses are infective conditions,” said Prof. Hakim. “And meningitis stands out as a very important problem.”

Several years ago, Prof. Hakim performed a study looking at meningitis in Zimbabwe. Out of 406 patients with clinical features of meningitis, 200 diagnoses were confirmed as indeed having meningitis —90 of those cases were Cryptococcal meningitis.

“We probably see something on the order of 600 to 700 cases of cryptococcal meningitis per year in a one thousand bed hospital, and this is using fairly crude diagnostic techniques, such as looking at the CSF [cerebral spinal fluid] and subjecting that to India ink —it’s only the occasional case who has cryptococcol antigen performed and even fewer would have cryptococcal cultures done,” he said.

And yet, when they examined hospital records from ten years earlier (before AIDS started having a major impact in the country), only one case of cryptococcal meningitis had been diagnosed that year.

Tuberculosis is also an important cause of meningitis in Africa and India and a major cause of focal lesions/tuberculomas — but even though mass lesions are an important problem in Africa, they are less well described and less commonly diagnosed due to the limited diagnostic capacity in most African settings, according to Prof. Hakim.

Dr José Vidal of the Emilio Ribas Institute of Infectious Diseases in Sao Paolo Brazil remarked on these differences as well (see table)

Table of some of the key pathologic studies from developing countries (adapted from Dr José Vidal’s slides)

In most of the pathologic studies from developing countries, “you can see the low proportion of cases of primary CNS lymphoma and… the relatively high percentage of CNS tuberculosis (TB) and bacterial infections [while in] studies from South America (most of them from Brazil) there is a predominance of toxoplasmosis and cryptococcosis and a few cases of primary CNS lymphoma.

In contrast, few studies from South America reported much CNS TB or bacterial infections,” said Dr Vidal, although a couple of recent studies in Brazil since the introduction of ART are now reporting more CNS TB.

Meanwhile, in India, according to Dr Manisha Ghate, Assistant Director of the National AIDS Research Institute in Pune, autopsy studies show a high rate of CNS lesions (79%, 38% of which were due to opportunistic infections). In cross-sectional studies from Southern and Western India, Cryptococcal meningitis, CNS TB meningitis and toxoplasmosis are also the most common opportunistic infections seen in people with HIV.

Finally, preliminary results from the inpatient substudy of the Asia Pacific NeuroAIDS Consortium Study (APNAC), conducted at eight sites throughout the region and presented by Dr Edwina Wright of the Alfred Hospital in Melbourne Australia, diagnosed a high rate (43%) of neurological disorders among 160 people with HIV who checked into one of the study sites.

These patients had very advanced disease (median CD4 cell count of 18 in 51 tested) and about a third were already on ART. Nonetheless, the most common diagnoses were cryptococcal meningitis (29%), cerebral toxoplasmosis (28%), TB meningitis (14%), seizures (7%), aseptic/bacterial meningitis (6%) and the remainder were strokes, spinal TB, tuberculomas and other conditions.

Prof. Hakim and other presenters later in the meeting highlighted the importance of strokes in the young (between 15 to 45 years of age) though the causes of stroke could vary by region. Investigations in Africa, suggest that in the context of HIV, most of these strokes appear to be linked to infective conditions such as cryptococcol disease or TB.

In one of these Indian studies that Dr Ghate described, a high number of strokes were attributed directly to HIV. Meanwhile, studies in the developed world suggest that HIV infection itself may cause subclinical atherosclerosis that increases the risk of stroke and cerebrovascular disease.

But the incidence of some infections also can vary greatly from one country to the next even within the same region. “People talk about the developing world or of Sub-Saharan Africa as if it were homogenous. Far from it,” said Prof. Hakim. For example, he noted that toxoplasmosis is a major problem in India, Asia and Brazil, and even nearby in South Africa.

But, “interestingly, in our own environment in Zimbabwe we’ve specifically looked for it and we’ve seen exceedingly few cases,” he said. “What is interesting is that some 40 or 50 years ago, there were surveys that were done by veterinarians and medical laboratory scientists in Zimbabwe, and the serological tests at that time showed that the prevalence of serological positive sera from both animals and patients was up to 30%, but currently we seem to see a lot less and I would really value any discussion on that.”

According to Dr Rezza, some factors probably do have a real effect upon the patterns of CNS disease such as differences in the circulation of specific infectious agents like Chagas disease and HTLV-1 and 2 that are common in South America but not elsewhere. Indeed, Dr Vidal and speakers from Brazil highlighted the growing importance of these emerging diseases in their region. Major epidemic coinfections such as hepatitis C virus — which data now suggest can also affect the brain — and malaria could also have an impact on neurologic disorders in people coinfected with HIV.

The case of malaria may provide one possible explanation for the low rates of toxoplasmosis seen in some of the malarial countries in Africa, since several of the drugs in widespread use to treat or prevent malaria, such as cotrimoxazole and Fansidar can also prevent toxoplasmosis.

The risk of CNS disorders could also differ according to whether a country’s HIV epidemic is generalised or limited to certain vulnerable groups. For example, Dr Rezza shared data from the Italian National AIDS Registry that suggested injection drug users (IDUs) were 50% more likely to present with HIV encephalopathy than non-IDUs. Interestingly, in some of the cross-sectional studies in India, where most of the early transmission of HIV in India was through injection drug use, there are very high rates of peripheral neuropathy, cranial neuropathies and stroke attributed to HIV — which suggests a greater likelihood of neurological problems among this population.

The impact of ART on CNS disease

Although most researchers also expect to see dramatic reductions in the incidence of CNS diseases with the rollout of ART, it’s unclear if the effect of treatment (which is often initiated late in the stage of disease) will be the same as in industrialised countries. Prof. Hakim worries that it could be difficult to measure the impact given the limited epidemiological data before the roll-out of ART. Furthermore, “there are only a few programmes that have the ability to document the variety of conditions in any consistent way.”

However, according to several other talks over the course of the meeting, the relative frequency of some disorders does not appear to be decreasing as much as hoped in patients on ART in some settings.

For example, Dr Vidal noted that although there had been a significant reduction in toxoplasmosis in Brazil, “the impact of HAART on the incidence of cerebral toxoplasmosis seems to be smaller in developing countries. The decrease of incidence was four-fold in France and five-fold in Spain but the corresponding figure in Brazil was only 50%. It is possible that the restricted access to health services and high proportion of cases that are not aware of his or her HIV serological status, are the main reasons of this different impact,” he said.

This could be because about one-third of those living with HIV in Brazil remain undiagnosed and thus are at high risk of opportunistic infections. In fact, in one clinical series from Sao Paolo, 35% of the patients diagnosed with toxoplasmosis had not previously known that they were HIV-positive.

Finally, an eye must be kept on differences in the actual ART regimens that will be used in one region to another. One of the other major debates at the meetings was whether different antiretrovirals used (some drugs penetrate the CNS much better than others) might affect different neurological outcomes. For example, the outpatient substudy of APNAC reported significantly lower rates of HIV-related cognitive impairment in patients taking CNS-penetrant ART.

What will the future hold?

In addition, over the course of the meeting, it became clear that a number of other new neurological problems are emerging in people despite ART, including conditions related to immune reconstitution inflammatory syndrome (IRIS), HIV leukoencephalopathy, and HIV-related cerebrovascular disease.

Finally, there appear to be preliminary indications of long-term neurological consequences to being HIV-infected in older people with HIV in Hawaii. It is possible that much of the HIV-related damage in the CNS prior ART treatment could be permanent, and that as people with HIV age, they could be more prone to developing an Alzheimer’s-like dementia disease. Nevertheless, the patterns that will emerge in developed countries may differ substantially from what will be seen in resource-limited settings, where optimal suppression of viral load is less likely because of poor access to second and third line ART regimens and viral load monitoring.

Other resources

The abstract book for the meeting can be downloaded from the conference website.

HIV & AIDS Treatment in Practice reviews of neuro-AIDS and diagnosis of HIV dementia in resource-limited settings.