New directions in HIV healthcare

Abstract

The Canadian Association for HIV Research (CAHR) is the professional organization for HIV and AIDS research in Canada or by Canadians. The theme of CAHR 2011 was “Honoring our history, embracing our diversity”, and highlighted the strengths that our diverse communities bring to the fight against HIV/AIDS, and more specifically, the important research data presented that reflect the new direction in which HIV research is focused: to regularize the daily life of the HIV-infected patients. Clinical research in the field of HIV has evolved from developing medication to ensure the patients’ survival, to the present where survival is assumed and life events are investigated. This article will cover the research presented in the clinical track and will focus on two issues that are going to impact the future of HIV-infected individuals: cognitive health and child conception.

Cognitive health

In the pre-HAART era, as HIV-infected individuals became more immunocompromised, HIV dementia was a true concern. The clinical picture was clear: low CD4 and signs of dementia were often seen in patients with advanced HIV infection. In the HAART era, cases of HIV dementia have drastically decreased, as people now have restored immune function. In parallel, there has been an increase in subtle cognitive deficits in individuals with a chronic HIV infection, but whose immune system has been restored through the use of antiretroviral medications (ARVs) [1].

Identifying these individuals who show signs of HIV-associated neurocognitive disorder (HAND) requires neuropsychological testing that depends on the availability of trained personnel to perform the testing. Mild forms of HAND often go by unnoticed until the individuals start experiencing difficulties in executing basic daily functions, or loved ones notice changes in behavior [2]. Early diagnoses of HAND would benefit the affected individuals, since early detection could lead to early intervention. A rapid screening test that can identify individuals who may have HAND is the goal of the team of Lesley K Fellows (McGill University, Quebec, Canada), in a presentation given by the lead author, Lisa Koski [3,4]. The team determined that the Montreal Cognitive Assessment (MoCA) on its own was too easy and patients were able to excel in the test; the test thus was not sensitive enough to detect the subtle cognitive deficits seen in those individuals who had HAND. The addition of a computerized test that tested many different neuropsychological spheres increased the sensitivity of detecting impairment in complex cognitive functions. Research is now continuing in trying to determine the best possible screening test for HAND.

One of the more prevalent views is that HAND may be associated with residual viral load present in the cerebrospinal fluid (CSF) and that using ARVs that have a higher affinity for crossing the blood-brain barrier may be protective [5,6]. Adriana Carvalhal (McMaster University, Ontario, Canada) and her team presented their work that looked at the impact of the type of ARV on neuropsychological testing results [7]. The study looked at 385 individuals from the Ontario HIV Treatment Network (OHTN) Cohort Study and their performance score on four neuropsychological tests; these scores were then compared with the individuals’ ARV profile. The antiretrovirals were assigned a CNS Penetration Score (CPE), which has been previously validated as a score that correlates to how well the medication penetrates the blood–brain barrier [8]. Their study showed that contrary to some previous studies, there were no associations between better performance on the neuropsychological tests and the CPE score. To add more confusion to the whole issue, some work carried out by Robin Hsiung et al. was presented that looked at the association between CSF viral load and performance results on the MoCA test and the Dementia scale [9]. Looking at seven individuals who had been referred to a specialty clinic that evaluates HIV patients with neurocognitive symptoms in British Columbia, Canada, the authors measure the plasma viral load and the CSF viral load. In six out of seven individuals, both viral loads were below the detectability level, and in the other individual, there was no viral load detectable in the blood, and only a very low level in the CSF. The authors thus concluded that the cognitive changes seen in the patients were possibly not correlated to the CSF viral load or viral replication, or that the CSF viral load does not adequately reflect viral activity in the brain.

Child conception

Amongst the many issues now facing the population of healthy HIV-infected individuals is the concept of procreation. Individuals now have a near-normal life expectancy when assiduously taking ARVs; the issues of having and raising children has become a reality. Considering that HAART has only been around for 15 years, we have no historical perspective on the effect of HIV on the next generation of children. Whereas the impact of the mother’s HIV infection with a detectable viral load on the fetus has been well established, there is a dearth of information pertaining to the impact of a mother’s chronic HIV infection (albeit with an undetectable viral load) and HIV medication on the progeny.

Helene C Cote (University of British Columbia, British Columbia, Canada) presented results of research that looked at the impact of ARVs on mitochondrial function in placenta [10]. Nucleotide reverse transcriptase inhibitors (NRTIs) are a class of ARVs that inhibit HIV replication via DNA polymerase and cause a chain termination. Mitochondria also harbor a similar enzyme, and thus can also be affected by NRTIs. The underlying concern is that in utero exposure to NRTIs could be detrimental to the fetus. The research involved 36 HIV-positive pregnant women who were under ARV treatment and were compared with 33 HIV-negative pregnant women with no exposure to ARVs. The research team looked at the electron transport chain, a group of proteins involved in the generation of ATP in the mitochondria, some of which are encoded by mitochondrial DNA (CIV), while others are encoded exclusively by nuclear DNA (CII). The expression of these proteins was compared between the placental and maternal sides, and between HIV-positive and HIV-negative mothers. The authors found no differences in protein expression, and thus, if there was any NRTI toxicity, it was not manifested in the expression of the proteins of the electron transport chain.

Children are being born to HIV-infected mothers at a greater pace and, as these children get older, there are still unanswered questions about the long-term impact of their mothers’ HIV infection or fetal exposure to ARVs. Forbes et al. presented data from the CARMA cohort (Children and women: Antiretrovirals and Markers of Aging) [11]. The purpose of the study was to assess the adverse health outcomes of HIV-exposed uninfected (HEU) children. The team followed 103 pregnant women in British Columbia, Canada, from 1990 to 2009. A total of 92% of these women had been taking ARVs, and the women were of diverse ethnic (21% aboriginal, 46% Caucasian and 20% black) and social backgrounds (35% were illicit drug users, 13% smokers, 2% alcohol users and 50% had no illicit substance use). Out of 103 HEU, 21 reported serious adverse health issues, ranging from serious infections to behavioral issues. The authors concluded that the most significant variables associated with the adverse health events were mostly associated with lifestyle of the mother (drug use and housing instability), and less related to HIV and ARV use.

Carole Gentile and her team at the University of Ottawa (Ontario, Canada), carried out another study on HEU [12]. They wanted to describe the characteristics of HEU children who had been diagnosed with autism at the HIV program of the Children’s Hospital of Eastern Ontario (CHEO). The team performed a retrospective chart review for the period 1997–2010; out of 161 HEUs, nine cases of autism were discovered (rate of 5.6%). Amongst the nine cases, seven had been exposed to ARVs (out of 153 HEUs exposed to ARVs, with a rate of 4.6%). These rates far exceed the population autism rate of 0.8–0.9%. The authors conclude that the biological plausibility may lie on mitochondrial toxicity: there has been recent data that have shown that there is a higher rate of mitochondrial dysfunction in people with autism. As earlier explained, NRTIs may induce mitochondrial toxicities, and may partially explain the higher rate of autism seen in HEU.

Conclusion

As the compendium of current ARVs now allows greater survival and increased life expectancy, new health issues are emerging. Liver disease has recently become a serious concern amongst HIV and specifically HIV–hepatitis C virus coinfected individuals. In the chronically infected HIV individuals, developing issues such as conception, aging-related health concerns and other comorbidities such as cardiovascular disease are becoming more important. Consequently, HIV research is now expanding beyond conventional HIV treatment, and focus is being directed towards lifestyle health issues, and innovative treatment such as vaccine therapy.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.