We focused on alcohol use because it is the most abused substance in sub-Saharan Africa, where 70% of PLWH reside globally, making this the substance use problem of greatest public health importance in the HIV population. However, we acknowledge that substance abuse varies by country and that a limitation of this review is that it does not address the occurrence of other important kinds of substance use among HIV-infected individuals.
There is strong and consistent evidence that alcohol use is associated with HIV incidence and prevalence in LMICs. A recent meta-analysis of studies in sub-Saharan Africa identified 35 studies with a summary odds ratio of 1.61 (95% confidence interval: 1.44 to 1.80).74 The association held among both high-risk groups and the general population and was stronger among heavier drinkers. There are several possible mechanisms for this association: the biological plausibility that heavy alcohol use increases susceptibility to and severity of HIV infection through effects on innate and adaptive immune system aspects, the central nervous system (CNS), the liver, and other organ systems; the direct effect of alcohol consumption on cognitive capacity and its disinhibiting effect on behavior, which can affect consistent condom use or the ability to negotiate safe sex; the co-occurrence of alcohol use and risky sexual behavior among individuals with risk-taking personality characteristics75; and the dual character of places that sell alcohol, which are also sometimes meeting spots for potential sex partners (Fig. 1).
In the ART era, the primary predictor of HIV-related mortality, morbidity, and treatment failure is nonadherence to ART.76 Systematic reviews have shown that alcohol use is strongly associated with poor adherence to ART,77,78 with alcohol users being around 50%–60% less likely to adhere to ART than nonusers. For example, a recent study from South Africa found that good adherence was reported by 65% of nondrinkers but only 39.7% of drinkers (P < 0.001).79 Adherence was lower still among hazardous or harmful drinkers (30.3%). The evidence for a causal effect of AUD on ART adherence is strengthened by dose–response and temporal relationships.79–82
The mechanisms by which alcohol consumption reduces ART adherence are similar to those that increase the risk of HIV acquisition, that is, cognitive factors (due to acute intoxication), personality factors (eg, risk taking), structural factors (eg, chaotic environment), and misconceptions about toxic interactions of alcohol use and ART.83 These factors can contribute to poor adherence when alcohol users taking medications off-schedule or missing doses, not renewing prescriptions, or having decreased access to ART.78,84
The primary evidence-based interventions to reduce AUD are structural interventions (eg, comprehensive policy measures to regulate the availability of alcohol and reduce demand through taxation and pricing mechanisms) and individual psychotherapeutic interventions (eg, screening and brief interventions by trained primary health care professionals). There have been few RCTs assessing the effects of psychotherapeutic interventions on alcohol use and ART adherence in HIV-infected alcohol users. One trial found a significant intervention effect on ART adherence and HIV virological and immunological outcomes at the 3-month follow-up, but not at 6 months,82 and a second trial found no significant intervention effects on adherence or virological endpoints.83,85 The difference may have been attributable to key variations between these trials, including the behavior change model used, the intensity and duration of the intervention, the type of counselor, the control condition, and the duration of follow-up. Another RCT found that a motivational enhancement intervention had a significant effect on HIV viral load at 6 months86 among PLWH aged 16–25 years, including a borderline significant reduction in alcohol use. Three other studies have evaluated the effect of motivational interview-based counseling on alcohol use among PLWH with AUD,87–90 but they did not measure ART adherence at HIV-related endpoints. Each of these studies found a large and significant intervention effect on alcohol use (Table 1). Further research is needed to refine and evaluate interventions to improve adherence among alcohol users in LMICs.
Further qualitative studies should be conducted to understand the role of alcohol in HIV acquisition through event-level data (eg, an in-depth examination of alcohol use and sexual activity occurring on particular occasions). Pilot studies are needed that would adapt alcohol-reduction interventions to suit HIV-infected populations in LMICs, followed by RCTs to evaluate the impact of such interventions on ART adherence and disease progression.
HAND is a general term that includes a number of disorders that are complications of HIV infection. The definition is based on the consensus opinion of experts in the field, and patients are diagnosed using a battery of neuropsychological tests.91 The term HAND includes asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia.91
HIV-associated dementia is the severe form of HAND. Prevalence in HICs has declined after the introduction of ART.92 HIV-associated dementia is characterized by subcortical dementia, which involves motor and cognitive slowing, with a neuropathology consistent with HIV encephalitis.49 Prognosis is poor and survival is usually less than a year.93
The prevalence of HAND in LMICs varies, ranging from 6% to 64% in children and adults99–106 (Table 1). Not all of the individuals in these studies were on ART, which could partially account for the variation. Other factors that may also explain the differing prevalence rates are people's HIV subtypes, which may contribute to more severe forms of HAND, as seen in some subtypes found in Uganda107,108; the increasing burden of comorbidities related to cognition such as stroke109; demographic, educational, and cultural differences; or differing approaches to measurement of impairment. Because treatment of HIV infection is often delayed in LMICs, the added burden of opportunistic infections mimicking HAND (eg, cryptococcal infection, tuberculosis, meningitis, or neurosyphilis) is also a possibility. Notably, in HICs, the norm is screening non-HIV populations with cognitive impairment for infections like syphilis.110 However, in LMICs, screening is neither routine for non-HIV populations nor for individuals with HAND, which could mean that the burden of HAND is overestimated and that treatable conditions are being neglected.111
Neuropsychological tests are pivotal to the definition of HAND but have several restrictions. First, the diagnosis by neuropsychological tests does not account for disease mechanism. Importantly, it does not differentiate between progressive disease directly associated with HIV infection and nonprogressive disease owing to HIV-associated insult to the brain.49 Including the latter cases could overestimate the milder forms of HAND. Second, neuropsychological tests should have at least the following neurocognitive domains: verbal/language, attention/working memory, abstraction/executive function, learning/recall, speed of information processing, and motor skills. However, the choice of domains used varies between the different tests.112–115 Third, normative data for healthy age- and sex-matched community controls, crucial for the interpretation of neuropsychological tests, are limited in LMICs. Furthermore, these neuropsychological tests should be validated for the target population's culture and language and administered and interpreted by appropriately trained professionals; this is not always the case in LMICs.49,116 Each neuropsychological test varies in length, and weighing the need for lengthy and more sensitive tests versus shorter and more conveniently administered tests is challenging. Currently, there is no consensus on the best approach.112 Although the development of standardized tools is important, linking these tools to biomarkers of HAND would make them dynamic and more specific. Biomarkers for HAND are currently in the process of being identified, and those related to monocyte activation (eg, CD14) have shown promising results.49 Depression and AUD overlap with cognitive impairment (Fig. 1); integrating a screening tool that encompasses both disorders may be an efficient way forward.110 This approach could reduce the time spent screening for these noncommunicable diseases separately in busy and overstretched ART clinics.
Despite the availability of numerous, albeit limited, neuropsychological tools, routine screening in ART clinics in LMICs is still not the norm. This could have important implications for people who have HIV–dementia but are not eligible to start ART based on their CD4+ T-lymphocyte cell count. HIV–dementia is an AIDS-defining illness and justifies starting ART.
Overall, ART has been beneficial for HAND in both HICs and LMICs. Eleven of 15 studies in a systematic review in 11 HICs and 4 LMICs showed improvement in neurocognitive status after treatment.111 The studies that showed no association were usually statistically underpowered and sometimes lacked appropriately matched normative data. Although ART may improve cognitive function in those with severe impairment, it does not seem to fully eradicate the milder forms of HAND.33,99,111,117,118
A multinational study evaluated the outcome of neurocognitive impairment and the degree of CNS penetration for 3 ART regimes (including WHO-recommended first-line treatments) in a large randomized trial.119 The study found no differences in the degree of CNS penetration of WHO-recommended ART regimens.119 Minocycline, a neuroprotective agent, was explored as an adjunct to ART in managing HAND in LMICs.120 Although this trial was unsuccessful, this should not discourage future trials from exploring the role of adjunctive neuroprotective/anti-inflammatory agents in reducing the burden of HAND.49
A prospective cohort study in Zambia showed that 495 PLWH who had recently commenced ART had cognitive impairment and poorer ART adherence.45 In HICs, mild neurocognitive impairment was associated with poorer quality of life, unemployment, worse medication adherence, lower driving ability, and reduced survival.121 Furthermore, HAND may also be associated with adverse HIV outcomes, including HIV resistance and poor ART adherence due to prospective memory impairment.122 Alcohol misuse may coexist in patients with HAND, which could also impact on adherence. However, the extent to which these factors play a role in HIV acquisition and disease progression in LMICs has yet to be completely understood.
Of high priority is the development and validation of a standardized neuropsychological test that is resource appropriate, culturally tailored, and includes biomarkers of HAND to improve specificity (Table 2). Well-powered studies with appropriate normative data that examine the effect of ART in a well-characterized cohort (with brain imaging, exclusion of opportunistic infections, and autopsy confirmation of underlying pathologies) are needed in LMICs. Ideally, longitudinal studies should have a follow-up beyond the longest observation period of 3 years to determine the long-term prognosis of HAND in the ART era. In the meantime, screening for HAND needs to be instituted in clinics in LMICs, especially for patients not otherwise qualifying for ART.
Existing research and care platforms could be harnessed to conduct MNS studies. New scientific collaborations could be established, for instance, with Demographic Surveillance Systems, such as those in the INDEPTH Network (www.indepth-network.org), and HIV research centers in LMICs, such as those supported by the UK Medical Research Council, the Wellcome Trust, and the US National Institutes of Health. Opportunities exist for incorporating MNS research into existing HIV research platforms. For example, researchers could use the IeDEA network, AIDS clinical trials group sites, the WHO STEPS surveys, and the African Partnership for Chronic Diseases. Challenges in implementing such research may include the lack of awareness among many HIV researchers, funders, and policymakers of the importance of mental health in addressing HIV/AIDS.
Strengthening research capacity in many LMICs that have exceedingly low numbers of specialists in neurology and psychiatry, a situation exacerbated by the ongoing brain drain, will be important. New initiatives are supporting capacity building in mental health research, particularly the research hubs in Africa, Asia, and Latin America funded by the US National Institute of Mental Health (www.fic.nih.gov/programs/Pages/medical-education), consortia funded through the UK Department for International Development (www.prime.uct.ac.za), and Grand Challenges Canada (www.grandchallenges.ca), which funds projects and rising investigators in global mental health. The US President's Emergency Plan for AIDS Relief/National Institutes of Health–funded Medical Education Partnerships Initiative (MEPI)123 is another potential platform on which to build research capacity in HIV mental health and neurology in Africa. Existing initiatives such as Fogarty International Center fellowships (http://www.fic.nih.gov/programs/pages/scholars-fellows.aspx) and Wellcome Trust international training fellowships (www.liverpoolwttc.org.uk) also fund research and training of investigators in global mental health and neurology. At an institutional level, mentorship schemes are needed to pair clinical academics in psychiatry and neurology with centers requesting support. Examples of specific training priorities include grant writing, qualitative methods, formative research, cross-cultural methods in psychiatry, clinical trials training, database management, and biostatistics.
Addressing the burden of MNS conditions among PLWH in LMICs will contribute significantly to health, social, and economic outcomes as ART is scaled up. We focused this review on the 3 key MNS conditions most prevalent in HIV populations in LMICs, based on the current literature. Epilepsy, stroke, peripheral neuropathy, psychotic disorders, anxiety disorders (including post-traumatic stress disorder), and illicit drug use are other MNS conditions that we did not discuss in this review, but that are important areas for future research in LMICs.
Limited access to psychiatrists and neurologists in LMICs has been a long-standing issue; mentorship and fellowship schemes at an individual and institutional level do exist, but they need to be further supported. In the short-term, task shifting in the care of MNS disorders in HICs and LMICs has been successful and should be integrated into routine HIV care in LMICs.
The authors would like to thank Jessica Healy for her help with the literature search and Dr. Sam Nightingale for helpful discussions on the HAND section.
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