NeuroAIDS in the Asia-Pacific Region

NeuroAIDS in the Asia-Pacific Region

July 19, 2007

Sydney, Australia

On July 19, 2007, a group of distinguished AIDS neurologists, psychiatrists, immunologists and virologists gathered at the Garvin Institute in Sydney, Australia, to begin a two-day workshop focused on the impact of HIV infection on the central nervous system on subjects with AIDS in the Asia-Pacific Rim region. This workshop was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) of the United States National Institute of Health, with additional support for participants provided through the AusAID program of the Australian Government. Development of the workshop was led by Drs. Jeymohan Joseph (NIMH) and Michael Nunn (formerly of the NINDS), who were joined in organizing of the workshop agenda by Drs. Bruce Brew (Sydney), Edwina Wright (Melbourne), Patrick Li (Hong Kong) and Kevin Robertson (Chapel Hill, NC). The workshop was an affiliated event of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, which it preceded. The workshop included members of the Asia-Pacific NeuroAIDS Consortium (APNAC) and many other investigators with interests in this region, spanning from India to Hawaii and Japan to Papua New Guinea.

Matthew Law of the Treat-Asia Cohort (TAHOD) study presented an overview of the AIDS epidemic as it currently stands in the Asia-Pacific region. HIV seroprevalence varies significantly, from low levels in countries such as the Philippines and Malaysia, to the relatively high levels of Papua New Guinea, where the level of HIV infection in the population is estimated at 1.8% and growing. Many HIV subtypes are found across the region, with HIV clades A and E found in Thailand, Cambodia, Vietnam, Myanmar; clade C in India, and clade B predominating in Japan, Taiwan and the Philippines. In this part of the world, HIV transmission is predominantly through intravenous drug use and sex work, and the most common AIDS defining illnesses observed are opportunistic infections of tuberculosis, pneumocystis pneumonia, and cryptococcis. A unique opportunistic infection, penicillosis, has also been seen in this region.

This regional overview set the stage for discussion of the neurological complications of HIV infection and the underlying mechanisms of these diseases. Ned Sacktor discussed the incidence of dementia in cohorts in the U.S. and Africa, where HIV clades differ. It remains unclear whether HIV clade differences also lead to significant differences in the incidence of HIV-associated dementia, or HAD. Development of an international HIV dementia scale, the IHDS, has helped in this analysis. His studies in Uganda indicate that subjects infected with HIV clade A who are not receiving antiviral therapy have a similar risk of HIV dementia when compared to a cohort of subjects infected with HIV clade B in the United States, analyzed before the development of effective combination antiviral therapies. Additional studies of the incidence of dementia in cohorts of subjects infected with other HIV clades are clearly needed. HIV clade C infection in particular is where there is some indication dementia may not be a risk. The risks of dementia from infection with HIV clade E and B/C recombinant viruses are not known.

Howard Gendelman followed with a discussion of the cellular basis of CNS damage from HIV infection. He described the role of the macrophage in this process and presented his most recent work using the macrophage as a possible “Trojan Horse” for delivering antiviral drugs in a nanoparticle formulation across the blood-brain barrier into the CNS. Dr. Gendelman also discussed his recent analysis of CSF from patients through proteomic techniques in the quest to identify unique markers of CNS damage.

Kate Cherry presented an overview of the pathogenesis and potential therapies for peripheral neuropathy. Neuropathies are an important complication of HIV/AIDS in the Asia-Pacific Rim region, similar to the rest of the world. While painful neuropathies are present in untreated subjects with AIDS, it is also clear that some of the neuropathy can be caused by the antiviral therapies themselves, in particular the deoxynucleoside compounds ddC, ddI and d4T. In addition, HIV protease inhibitors, such as indinavir, have also been linked to neuropathy. In fact, 6% of HIV negative subjects given antiviral therapy showed neuropathy symptoms within six weeks of the initiation of treatment. For those with HIV-induced neuropathies, viral isolates do not appear to differ between those with the syndrome and those who remain free of symptoms. Host factors are likely most important for determining risk of disease, such as the presence of inflammatory cytokines. Unfortunately there are limited therapeutic options for treating neuropathies, including lamitrogen, recombinant NGF (not currently available) and possibly smoked cannibis. New therapeutic leads include the use of the capsaicin patch and oral flupirtine.

David Clifford closed the introductory session with a discussion of opportunistic infections of the CNS in AIDS. Opportunistic infections can be the leading cause of death for AIDS patients, particularly in resource-poor settings. Key issues include diagnosis, which can be costly, delivery of therapies, and initiation of antiretroviral therapy (ART). One possible complication is immune reconstitution syndrome, or IRIS, which can be activated upon induction of ART. Several infections of the central nervous system are of particular concern due to the high morbidity: progressive multifocal leukencephalopathy (PML), Cryptococcal meningitis and toxoplasmosis. The pathogenesis of each of these diseases and possible therapeutic approaches were presented. Therapies for these infections can be expensive and of limited availability, and early diagnosis and initiation of ART may be critical, as long as IRIS is not detected.

The introductory program was followed by sessions discussing the epidemiology and natural history of NeuroAIDS in each region represented at the meeting, as well as presentation of specific research programs ongoing in these areas. Dr. Darma Imran presented his experiences in Indonesia. MRI facilities are available in Jakarta to assist with the diagnosis of CNS disease. The predominant diagnosis for his AIDS patients is toxoplasmosis (39%), followed by tubercular meningitis (23%) and cryptococcal meningitis (13%), with 20% undetermined. He recommended a study of high dose fluconozole as a therapeutic approach for cryptococcal meningitis, where amphotericin is not available. Given the incidence of neurological disease in this AIDS patient population, he is also planning to train non-neurologists with basic neurological skills to help with the diagnosis of the neurological complications of HIV/AIDS. This training should facilitate earlier diagnosis of these conditions with the potential for saving lives.

Dr. Goa Tau discussed the distressing situation in Papua New Guinea (PNG), a resource-poor country with a population of 6.5 million and an HIV seroprevalence rate that is predicted to rise to 5% by 2012. Neurological examination and cognitive function testing of 33 HIV-positive patients showed 18% with HIV dementia and 26% with neuropathy. Both numbers are slightly higher than the rates seen throughout the APNAC group, but the differences are not considered likely to be significant. These results indicate that, so far, NeuroAIDS in PNG does not present a different picture than that seen in most regions. One unusual opportunistic infection case was presented.

Chakrin Nabangchang presented results from following a cohort of over 100 pediatric AIDS patients in Bangkok, Thailand. In this cohort, 12% had neurological symptoms, with only a few exhibiting developmental delay. This is an interesting result and is in contrast to the progression of neurological development seen in children living with AIDS in other settings. Whether this difference is due to HIV clade (likely clades A and E) or host genetic differences remains to be tested.

Jim Neaton presented the ongoing efforts of the NIAID-supported International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), a large network of community-based HIV/AIDS clinics. This network has many international collaborators, including sites in the Asia-Pacific region. Both the SMART and START clinical trials were discussed. Dr. Neaton highlighted the importance of including neurological analyses when initiating large clinical studies such as those performed within the INSIGHT.

Another example of the power of networks was demonstrated by Dr. Edwina Wright, who presented the results of studies performed within the APNAC group. 8.3 million in the Asia-Pacific region are infected with HIV, with over 1 million at risk of developing neurological illness. Only 16% of those in the region who need ART are able to receive it. APNAC includes 10 sites within 7 of the countries in the region. A study of 160 HIV-positive subjects found 43% with a neurological diagnosis. Opportunistic infections diagnosed included cryptococcal meningitis (29%), toxoplasmosis (28%) and tubercular meningitis (20%). In the outpatient group, 12% demonstrated significant cognitive impairment, 20% exhibited signs of neuropathy and 36% were depressed. In this study, as elsewhere, neuropathy was associated with exposure to deoxynucleoside antiviral therapy. Dr. Wright emphasized the importance of obtaining normative data for proper analysis of neurocognitive test data in such varied clinical settings and test populations.

The afternoon session started with China, and Bob Heaton presented a summary of the studies that he and his colleagues have performed in the Yunnan and Anhui provinces. The main risk of HIV in Anhui is associated with prior blood donation, while in Yunnan there is a high level of intravenous drug use. The clinical picture of NeuroAIDS in these settings is similar to that in the U.S. prior to the introduction of ART. Daily living is affected for all HIV-positive subjects, regardless of whether tests indicated clear neurocognitive impairment. Hepatitis C infection is also high and correlates with impairment, and depression is also a significant problem in these regions. Dr. Lucette Cysique presented preliminary findings that indicate gender may be almost as large a factor for cognitive impairment as HIV sero-status. This effect may be due to HCV infection, which was found to be higher among the women.

Patrik Li discussed the picture of HIV and NeuroAIDS in Hong Kong. There is a low sero-prevalence in the city (0.1%). The picture of neurological complications is similar to that in the U.S., and there were clearly poorer outcomes for those patients with neurological disease. Iris Chan briefly presented results from a study of 174 HIV seropositive subjects, with results very similar to those presented by Dr. Heaton, with an association between the global depression score and impairment. HCV infection was low in this population.

Dr. Shinichi Oka discussed HIV infection and CNS complications as seen in Japan, where the situation is very similar to that seen in the United States and Europe:  HIV clade B predominates and there is widespread availability of ARVs. He did highlight however that those patients that do appear with neurological complications of HIV infection have a very high mortality. Dr. Oka also presented intriguing results of host genetic analysis and response to the non-nucleoside reverse transcriptase inhibitor efavirenz. In his study group, subjects homozygous for the star allele of CYP2B6 had higher blood levels of drug and experienced the vivid dreams that have been reported with this therapy. Reduction of the efavirenz dose eliminated the dreams, but was sufficient to maintain viral suppression in these patients.

Jeremy Day of Oxford University presented findings from a cohort study ongoing at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. IV drug use is high among the HIV-positive subjects in this study, and there is a high incidence of tuberculosis in the population (189 cases per 100,000). Where tuburcular meningitis is found, there is 100% mortality. Also, multi-drug resistant TB presents a particular challenge – 12% of HIV-positive patients had MDR TB, compared to 4% of the HIV-negative TB meningitis patient group.

At this point in the workshop, the emphasis shifted away from discussion of disease outcomes, patient populations and possible approaches to therapy and focused in on training. Roger Detels described his International Clinical, Operational and Health Services Research and Training Award (ICOHRTA) program in China that has been developed to train clinical research scientists for the study of AIDS and TB. 

Following Dr. Detels presentation, there was a roundtable discussion of how to build clinical research capacity in situations where there may be significant financial or human resource challenges. Panelists included presenters Detels and Clifford, as well as Avindra Nath from Johns Hopkins, Shiing-jer Twu from Taiwan and Jeanne McDermott from the Fogarty International Center at the NIH. Clifford highlighted opportunistic infections, where mortality is high and availability of drugs is limited. Dr. McCutchan in the audience also raised the issue of proper diagnosis, where training plays a major role. Proper pathology and availability of autopsies was also difficult, sometimes for cultural reasons. In India this has been a particular problem, although there has been some progress noted in Bangalore. In Malaysia and other areas this has been more difficult. Funding for training is not always the major impediment, but where there is a low incidence of HIV the investment may not be a priority. Dr. Clifford noted the need for lumbar punctures to make an accurate diagnosis of CNS opportunistic infections where there is an HIV-positive subject presenting with a headache. Training for use of the PCR test might help bring lumbar punctures into more routine practice in the neurology clinics. Availability of cryptococcal antigen tests was also highlighted.

In the discussion, Dr. McDermott emphasized the need for a philosophy of training, which should be across disciplines. She also noted that training was necessary, but not sufficient, since in many settings other significant barriers exist to providing patient care and providing diagnosis and treatment. Detels echoed this, noting that the major problem is infrastructure. Drugs for treatment are often available, but there is insufficient trained manpower to deliver the therapies. The disparity between rural and urban settings is also an issue. It is important to develop diagnostic algorithms that are appropriate for settings where less health care is available. Surrogates for viral loads would be helpful, and simplified tests for opportunistic infections. Use of the internet for training, even in some remote settings, is another possibility that should be considered.

Dr. Nath added that research in CNS opportunistic infections is currently almost nil, yet mortality even in the U.S. remains high. He noted that understanding IRIS may also be important, since even a rare case where ARV therapy leads to death might generate a backlash against ARV use in certain populations. Understanding and prevention of IRIS is important. It is also not clear what effects of opportunistic infections in the CNS might linger even after therapy. As raised by Dr. Oka’s presentation, understanding host genetic factors for CNS disease is also important. Dr. Twu described the situation in Taiwan, and noted that training in neuropathogensis is a problem. Early detection of these complications is important, as is the prevention. He also noted that there is not enough training in the use of behavioral tests that are important for the diagnosis of cognitive impairments. It was also noted that research projects in these settings support the capacity building efforts.

The second day of the workshop began with a video presentation from Dr. Sunil Ahuja focusing on the host genetic factors involved in neuropathogenesis of HIV. His work on MIP1alphaP, CCR5 and CCL3L1 was discussed. The hope is that host genetics may be useful in predicting individual patient responses to ART.

This plenary talk was followed by several presentations focused on India. Dr. Mahendra Kumar presented a summary of the AIDS epidemic as it stands in the country. He also discussed the cultural aspects of Indian life that underlie the risks for the spread of HIV. Describing a study of 200 subjects from Chandigarh, it was concluded that the picture of opportunistic infections is similar to those seen elsewhere, with tubercular and cryptococcal meningitis, PML and toxoplasmosis.

Dr. Satischandra of the NIMHANS institute described his work with patients in Bangalore, where 144 subjects with neurological complications of HIV infection were seen in the past year. 84% of patients suffered with the same opportunistic infections seen in Chandigarh. For cryptococcal meningitis, the mortality decreased from 50% to 20% with the implementation of early diagnosis and aggressive treatment. Toxoplasmosis mortality has also been reduced to 13% with the availability of effective therapies. One striking characteristic of the patient population in Bangalore: diagnosis of dementia is very low at 1.4%. This may be due to clade differences, as most of these patients are infected with HIV clade C.

Tom Marcotte initially echoed this finding, as his studies put HAD at 6% in his study population in Pune with 35% of the HIV positive subject testing cognitively impaired. This is about half of the expected rate of impairment. Marcotte noted that the patterns of impairment in this population appeared to vary significantly, with impairment showing in different domains of cognitive function for different subjects. Once cognitive test norms were available from the testing of HIV negative subjects, the rate of neurocognitive impairment in the HIV-positive subjects increased substantially, approaching the levels reported for an ARV naïve HIV-positive population in the U. S.

Pankaj Seth changed gears slightly, presenting his studies of neuronal progenitor cells from the National Brain Research Center in Manesar, India. Using clade C HIV virus, he found infected cells did not produce the neurotoxin that had been found previously using HIV clade B. Future studies will focus on the viral target responsible for these clade differences.

The final regional session of the workshop covered studies underway in Thailand, where HIV Clade E is predominant. Victor Valcour of the University of Hawaii presented his joint studies with investigators at the Pramongkutklao Military Hospital in Bangkok. A study of 60 subjects, 15 with HAD; 15 age, gender and CD4 matched HIV-positive controls; and 30 HIV-negative subjects was initiated. The progress of HIV-positive subjects was followed for one year after initiation of HAART therapy. Initial results from this cohort found that subjects with HAD were more likely to have elevated HIV levels in circulating monocytes, confirming results from a similar study performed in Honolulu using subjects infected with HIV Clade B virus. CD14/16 cell numbers were elevated in both HAD subjects and the controls, suggesting a significant level of constitutive monocyte activation in this population, even in the absence of HIV infection.

Cecilia Shikuma provided an update of studies in the South East Asia Research Collaboration with Hawaii (SEARCH) cohort. This effort includes the University of Hawaii and the Thai Red Cross AIDS Research Centre (TRCARC) and Armed Forces Research Institute of Medical Sciences (AFRIMS), both in Bangkok, Thailand. SEARCH will perform clinical and translational research in HIV/AIDS, providing a regional training center for HIV/AIDS patient care and management. SEARCH NeuroAIDS studies include: an analysis of neurocognitive norms for Thailand (SEARCH 002); a 3-arm clinical study to evaluate d4T toxicities (lipoatrophy, peripheral neuropathies) in GPOVIR, GPOVIR-Z (AZT substituting for d4T in the cocktail), or a combination 6 month GPOVIR/ 6 month GPOVIR-Z treatment approach (SEARCH 003); a neurocognitive study, including MRI imaging, in long-term viral load suppressed Thai subjects with or without dementia (SEARCH 005); and a study of T-cell correlates to HAD (SEARCH 007). 

Dr. Pasiri Sithinamsuwan provided an overview of the AIDS epidemic in Thailand, where 1-2% of the population is currently infected with HIV. Analysis of over 101,000 AIDS cases reported from 1994-1998 showed that some of the main killers were opportunistic infections of the CNS, with 25% tuberculosis, 18% cryptococcal meningitis, and 3% toxoplasmosis. Opportunistic infections have decreased significantly with the institution of ART therapy, but stroke, PML and CNS lymphoma (all less common in this population) have not been significantly affected. A clinical trial of trimethoprim-sulfamethoxazole as a less expensive alternative for treating toxoplasmosis was presented, however it was not found to be better than pyrimethamine-sulfadiazine. Key to accurate diagnosis in this hospital setting is MRI imaging, which allows differentiation of PML, lymphoma, toxoplasmosis and other conditions. CSF analysis is also important, and molecular diagnostic tools can help establish an accurate diagnosis when they are available.

Kevin Robertson ended the session with a discussion of the ongoing international adult AIDS clinical trials group (ACTG) study A5175. This study will eventually enroll 850 subjects from sites around the world to evaluate the neurocognitive impact of three different ARV treatment regimens. HIV clades A/E and C are the most common worldwide, yet very little is known about the impact of these viruses on the function of the brain and whether antiviral therapies will help. So far 112 subjects have completed the 48-week follow-up in the study.

The final scientific session of the workshop focused on emerging topics for future research in NeuroAIDS with a focus on the Asia-Pacific region. The session started with a presentation from Dr. Avindra Nath on the pathobiology of immune reconstitution syndrome, or IRIS. IRIS can occur in AIDS patients with or without a previous diagnosis of an opportunistic infection, and usually occurs after initiation of HAART. Only half of cases appear within 50 days of the initiation of therapy. The risk factors for developing IRIS and a case study were presented. Dr. Nath also discussed the role of T-cell infiltration and the possibility that HIV-tat protein might play a role through stimulation of granzyme B activity in infiltrating lymphocytes.

Davey Smith presented an HIV genetic analysis and clade diversity with a potential relationship to CNS disease. Given the emergence of recombinant viruses across clades in sub-Saharan Africa, the potential for new viral variants to emerge with altered pathogenic properties remains high.

Bruce Brew focused on unique diseases of the Asia-Pacific region with the potential for expansion in immune-compromised individuals and possible complications of neurologic diagnoses. The possibility of spreading opportunistic infections such as Nipah and Japanese encephalitis was raised. Other conditions discussed included vascular disease and stroke, which may be particularly high in those populations where risk factors for these diseases are present. Metabolic diseases and/or exposure to toxic agents (examples: botulism, arsenic, copper deficiency) might be under appreciated as complicating factors in HIV-infected individuals in this region.

For the final presentation, Christina Marra discussed the problem of syphilis as a co-factor for HIV-positive patients. China in 2005 reported more than 100,000 cases of syphilis. In a recent University of Washington study, 15% of syphilis patients had neurosyphilis. By analogy, neurosyphilis will likely be an expanding problem among HIV-infected subjects in the Asia-Pacific region. Early lumbar puncture is important for testing for infection and initiating aggressive therapy to fight neurosyphilis. It appears that a serum RPR test can serve as a surrogate for follow-on lumbar puncture -- patients without normalization of serum RPR levels should receive a lumbar puncture to evaluate persistent infection of the CNS.

Following the scientific presentations, Dr. Jeanne McDermott of the Fogarty International Center at NIH and Dr. Yuan Liu of NINDS presented opportunities for funding for international investigators. Programs discussed included the AITRP, ICOHRTA AIDS/TB, and F05 programs. The NIMH/NINDS joint RFA “Mechanisms of HIV Neuropathogenesis: Emerging Domestic and Global Issues (R01)” (RFA-MH-08-030) was also highlighted.

The workshop was concluded with a summary of the sessions. Dr. Clifford noted that neuropathies and opportunistic infections remain a significant source of morbidity for HIV-infected individuals in the region. Dr. Brew added that many patients, in Jakarta for example, present very late in their illness, contributing to a high rate of mortality from these treatable diseases. Dr. Gao Tau commented that this was particularly the case in Papua New Guinea and is likely true in other resource poor settings. Dr. Nabangchang added that the situation in Thailand was not much different. Perhaps the INSIGHT network would be an opportunity for studies of this phenomenon, or for education about the problem of opportunistic infections in the CNS.

Dr. McCutchan raised the interesting problem of high HCV infection rates in China, and in particular, the gender disparities there. He commented on the continuing need for strong epidemiological studies in the region. It was also noted that where education was similar, neurocognitive norms were similar. McCutchan highlighted the need for careful consideration of normative cognitive function data and for obtaining norms where standard norms available for a given exam may not apply. But where would funding for obtaining this normative data come from?  McCutchan also highlighted the Oxford/Vietnam collaboration as an extraordinary example of what can be accomplished in a resource-poor setting, where inclusion of the microscopic observation drug susceptibility (MODS) assay could help with the rapid diagnosis of tubercular meningitis. The ICOHRTA effort in China, training policy makers in the issues surrounding HIV/AIDS, also had significant impact leading to a turnaround in countrywide policies.

In summarizing the work in India, Dr. Major noted the outstanding difference for HIV Clade C and the relative lack of HAD among AIDS patients there. The NIMHANS studies and ongoing neurological studies in Pune, Chandigarh and Bangalore will be watched with continued interest. Steve Wesselingh summarized the session on Thailand, noting the studies showing different communities had different exposures to infectious agents, and opportunistic infections are still the major burden of disease. HIV DNA reservoirs are an important ongoing area of research interest. For clinical trials in the Asia-Pacific region, it is clear that neurocognitive endpoints need to be included as protocols are developed.

Dr. Edwina Wright concluded the workshop by summarizing the final session. The incidence of IRIS is still unclear and needs more effort, and unique disease conditions are important to consider for their impact on CNS function in AIDS populations. Collaboration is a good strategy for these studies. The need for neurocognitive norms for resource-poor settings was reiterated. In addition, development of treatment algorithms for shortening diagnoses will be critical for saving lives. Stigma is of course a persistent problem.  It may be useful to develop a “NeuroAIDS for Dummies” document or CD for distribution through the World Neurology Foundation. Michael Ziskind added that advanced technologies, such as spectroscopy or MRI imaging, need to be more widely disseminated. Finally, an observer from the audience closed with a sobering note moving forward: there are neurologists in this region, but they are not engaged in treating NeuroAIDS. The key to successes here will lie in educating those caregivers.