Skip to main content
. 2014 Oct 23;1(11):938–952. doi: 10.1002/acn3.131

Table 1.

Clinical trials for adjuvant therapy of HAND since 1 January 1996

Trial and design Case definitions Target population (key inclusion and exclusion criteria) Objective of trial Dose selection Primary outcome Selected covariates and confounders Study duration
a.Rivastigmine(Simioni et al.)25 Randomized, double-blind, placebo-controlled crossover studyn = 17 Frascati criteria HAND: MND or HAD Assess safety and efficacy to treat HAND in a cohort of aviremic HIV-infected subjects. Based on studies in Alzheimer’s Disease; 1.5 mg/day increased every 2 weeks to 3, 4.5, 6, 9, and 12 mg/day 20-week change in absolute Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) HAND: 100% MND 20 + 6 weeks wash out + 20-week crossover
Age: not specified Sex: 71% male
ART: not specified, but all enrolled on ART. Age (mean ± SD): 55.1 ± 9.7 years
CD4 count: not specified Race/Ethnicity: not reported
VL: undetectable VL in plasma (<20 copies/mL for 3 months) and CSF (<200 copies/mL) Education (mean ± SD): 12.6 ± 2.8 cells/mm3
Duration HIV+ (mean ± SD): 14.2 ± 7.1 years
CD4 count (mean ± SD): 669 ± 222 cells/mm3
CD4 nadir (mean ± SD): 177 ± 100 cells/mm3
Plasma VL: 100% undetectable
Injection drug use: active use excluded
Karnofsky Score: not reported
b.Minocycline (Nakasujja et al.)27 Randomized, double-blind, placebo-controlled study (NS32228)n = 73 MSK staging HAND: ADC stage 0.5 or 1, with International HIV Dementia Scale <10 Assess the efficacy, tolerability, and safety of minocycline for the treatment of HAND in Ugandan ART-naïve subjects. Not discussed 24-week change in absoluteneurocognitive composite z-score measured by the Uganda Neuropsych Test Batterya Summary Measure HAND: 99/1% ADC 0.5/1 24 weeks RCT + 24 weeks open label
Age: 18–65 years Sex: 10% male
ART: naïve Age: 18–65 years
CD4 count: 250–350 Race/Ethnicity: 100% black, Ugandan
VL: not specified Education: 79% with ≤10 years
Duration HIV+: not reported
CD4 count (mean ± SD): 320 ± 52 cells/mm3
CD4 nadir: not reported
Log10 Plasma VL: 4.50 ± 0.73 copies/mL
Injection drug use: not reported
Karnofsky Score: 100% with ≥80
c.Minocycline(Sacktor et al.)28 Randomized, double-blind, placebo-controlled study (ACTG)n = 107 MSK staging HAND: Cognitive impairment with progressive decline, stratified based on subjective versus objective criteria. Assess safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment. Not discussed 24-week change in absolute NPZ-8b score HAND: 4/51/38/7% ADC 0/0.5/1/2 24 weeks
Cognitive impairment: ≥1 SD below norm on ≥3 tests, or ≥2 SD below norm on 1 test + ≥1 SD below norm on a 2nd test Ages: 18–65 years Sex: 89% male
ART: stable regimen for ≥6 weeks Age (mean ± SD): 51 ± 7 years
CD4 count: not specified Race/Ethnicity: 55/45% white/black
VL: stratified based on CSF VL (<30 copies/mL, ≥30 copies/mL, not measured) Education (mean ± SD): 14 ± 3 years
Duration HIV+: not reported
CD4 count (mean ± SD): 543 ± 283 cells/mm3
CD4 nadir (mean ± SD): 270 ± 254 cells/mm3
Plasma VL <30 copies/mL (mean): 86%
Injection drug use: 76% never use, active use excluded
Karnofsky Score: not reported
d.Memantine(Schifitto et al.)12 Randomized, double-blind, placebo-controlled study (ACTG 301)n = 140 MSK staging HAND: ADC stage ≥1, stratified on ADC stage. Assess the safety and efficacy of memantine as treatment for HIV-associated cognitive impairment. Not discussed 16-week change in percent NPZ8b HAND: 76% ADC 1 16 weeks
Ages: not specified Sex: 90% male
ART: stable regimen for ≥6 weeks, stratified on zidovudine use (never, previous, current) Age (median [95% CI]): 43 (31–63)
CD4 count: not specified Race/Ethnicity: 72% white
VL: not specified Education: 34% ≤12 years
Duration HIV+: not reported
CD4 count (median [95% CI]): 274 (4–1496) cells/mm3
CD4 nadir: not reported
Plasma VL (median): 112 copies/mL
Injection drug use: 82% never use
Karnofsky Score: not reported
d1.Memantine(Zhao et al.)29 Randomized, double-blind, placebo-controlled study, open-label extension phase of above12 (ACTG 301)n = 99 MSK staging HAND: ADC stage ≥1 Provide further safety and efficacy information on long-term memantine use as adjuvant therapy in HAND. Not discussed 12-week absolute change in NPZ8b score following 20 week original randomized trial. HAND: not reported Up to 60 weeks open-label extension.
Ages: not specified Sex: 90% male
ART: stable regimen for ≥6 weeks Age (median [95% CI]): 43 (37–49)
CD4 count: not specified Race/Ethnicity: 75/10% white/black
VL: not specified Education: 30% ≤12 years
Duration HIV+: not reported
CD4 count (median [95% CI]): 316 (189–473) cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Injection drug use: 84% never use, no active
Karnofsky Score (median [IQR]): 80 (70, 90)
e.Selegiline Transdermal System (STS)(Schifitto et al.)30 Randomized placebo-controlled study (ACTG 5090)n = 128 MSK staging HAND: Any cognitive impairment. Stratified ADC stage (0.5 vs. ≥1). Assess safety, tolerability, and efficacy of STS for the treatment of HAND. Not discussed 24-week change in absolute NPZ6c HAND: 34/62% ADC 0.5/1–2 24 weeks
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. Ages: not specified Sex: 88% male
ART: stable regimen, duration/type not specified Age (median): 45 years
CD4 count: not specified Race/Ethnicity: 51/36% white/black
VL: stratified on VL (<200 copies/mL, ≥200 copies/mL) Education (median (IQR)): 13 (12, 16)
Duration HIV+ (median (IQR)): 9.3 (5.5, 14.7)
CD4 count (median (IQR)): 422 (261, 691) cells/mm3
CD4 nadir: not reported
Plasma VL: 35% with <50 copies/mL
Injection drug use: not reported
Karnofsky Score: 77% with ≥80
e1.Selegiline (STS)(Schifitto et al.)31 Substudy of above randomized placebo-controlled study30 (ACTG 5090)n = 62 MSK staging HAND: Any cognitive impairment. Stratified ADC stage (0.5 vs. ≥1). Assess effectiveness of STS in reversing HIV-induced metabolic brain injury (measured by magnetic resonance spectroscopy, MRS) and in decreasing oxidative stress (measured by CSF [protein carbonyl]) Not discussed 12- and 24-week changes in MRS metabolite ratios HAND: 40/52/8% ADC 0.5/1/2 24 weeks
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. Ages: not specified Sex: 87% male
ART: stable regimen, duration/type not specified Age (median): 46 years
CD4 count: not specified Race/Ethnicity: 39/55% white/black
VL: stratified on VL (<200 copies/mL, ≥200 copies/mL) Education (median): 12
Duration HIV+: not reported
CD4 count (median): 361–384 cells/mm3 across treatment groups
CD4 nadir: not reported
Plasma VL: 77% with <50 copies/mL
Injection drug use: not reported
Karnofsky Score: 69% with ≥80
e2.Selegiline (STS)(Evans et al.)32 Open-label treatment phase of above randomized placebo-controlled study30 (ACTG 5090)n = 86 MSK staging HAND: Any cognitive impairment. Stratified ADC stage (0.5 vs. ≥1). Provide long-term safety (primary aim) and efficacy (secondary aim) of STS for the treatment of HAND. Not discussed 24-week change (open-label period only) in absolute NPZ6c. HAND: not reported 24 week open-label extension
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. Ages: not specified Sex: 86% male
ART: stable regimen, duration/type not specified Age (median [IQR]): 46 (42, 52) years
CD4 count: not specified Race/Ethnicity: 51/33% white/black
VL: stratified on VL (<200 copies/mL, ≥200 copies/mL) Education (median): not reported
Duration HIV+: not reported
CD4 count (median): 414 cells/mm3
CD4 nadir: not reported
Plasma VL: 36% with <50 copies/mL
Injection drug use: not reported
Karnofsky Score: 80% with ≥80
f.Selegiline (STS) (Sacktor et al.)33 Randomized, double-blind, placebo-controlled pilot studyn = 14 MSK staging HAND: Any cognitive impairment. Obtain preliminary data to assess safety, tolerability, and impact of transdermal selegiline on HAND. Based on in vitro study of oral selegiline demonstrating synthesis of neuronal antiapoptotic genes in injured neurons. Whether or not the subjected completed the study on the original dose of medication. HAND: 57/36/7% ADC 0.5/1/2–3 10 weeks
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test Ages: ≥18 years Sex: 71% male
ART: stable regimen for ≥6 weeks Age (mean): 42 years
CD4 count: not specified; Race/Ethnicity: 57/43% white/black
VL: not specified Education (mean): 12.2 years
Duration HIV+ (mean): 5.7 years
CD4 count (mean): 294 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Injection drug use: not reported
Karnofsky Score (mean): 81
g.Deprenyl (Selegiline) and thioctic acid(The Dana Consortium 1998)34 Randomized, double-blind, placebo-controlled, 2 × 2 factorial designn = 36 MSK staging HAND: Any cognitive impairment. Assess safety, tolerability, and impact of deprenyl and thioctic acid on HAND Deprenyl dose chosen to incompletely inhibit monoamine oxidase type B. Thioctic acid dose selection not discussed. Whether or not the subjected completed the study on the original dose of medication. HAND: 8/61/25/6% ADC 0/0.5/1/2–3 10 weeks
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. Ages: ≥18 years Sex: 72% male
ART: stable regimen for ≥6 weeks Age (mean): 41.2 years
CD4 count: not specified Race/Ethnicity: 55/33% white/black
VL: not specified Education (mean): 13.4 years
Duration HIV+ (mean): 5.7 years
CD4 count (mean): 208 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Injection drug use: not reported
Karnofsky Score: not reported
h.Valproic acid (VPA)(Schifitto et al.)13 Randomized, double-blind, placebo-controlled pilot studyn = 22 Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. HAND: not specified. Stratified on impairment (unimpaired vs.impaired) Assess safety and tolerability of VPA and explore its effect on cognitive performance and brain metabolism Not discussed 10-week difference in tolerability between VPA and placebo. HAND: 73/27% impaired/unimpaired 10 weeks
Ages: not specified Sex: 77% male
ART: not specified Age (mean): 43.5 years
CD4 count: not specified Race/Ethnicity: 45/55% white/black
VL: not specified Education (mean): 12 years
Duration HIV+ (mean): 9.4 years
CD4 count (mean): 434 cells/mm3
CD4 nadir: not reported
Plasma VL: 45% with <50 copies/mL
Injection drug use: not reported
Karnofsky Score (mean): 90
i.Lithium (Li)(Letendre et al.)35 Single-arm, open-label pilotn = 8 AAN criteria HAND: MCMD or HAD Determine the effects of low-dose oral Li on neuropsychological performance of people diagnosed with HIV-associated neurocognitive impairment Not discussed 12-week difference in absolute global deficit score (GDSd) HAND: AAN categories not reported. Mean GDS = 0.74 12 weeks
Age: 18–65 years Sex: 88% male
ART: stable regimen for ≥12 weeks Age (mean): 44 years
CD4 count: <500 cells/μL preferred but not required. Race/Ethnicity: 50/12.5% white/black
VL: <400 copies/mL in plasma and CSF preferred but not required. Education (mean): 14 years
Duration HIV+: not reported
CD4 count (mean): 292 cells/mm3
CD4 nadir: not reported
Plasma VL: 87.5% with ≤400 copies/mL
Injection drug use: active psychoactive drug abuse excluded
Karnofsky Score: all ≥50
j.Lithium (Li)(Schifitto et al.)14 Single-arm, open-label pilotn = 15 Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. HAND: Any cognitive impairment Assess safety and tolerability of Li and explore its effect on cognition, function, and neuroimaging biomarkers. Not discussed Proportion of subjects who completed 10 weeks of treatment at the originally assigned dose of Li. HAND: not reported 10 weeks
Age: not specified Sex: 67% male
ART: stable regimen for ≥8 weeks Age (mean ± SD): 47.5 ± 5.5 years
CD4 count: not specified Race/Ethnicity: 60/40% white/black
VL: not specified Education (mean ± SD): 11.2 ± 1.4 years
Duration HIV+ (mean ± SD): 12.1 ± 5.4
CD4 count (mean ± SD): 329 ± 207 cells/mm3
CD4 nadir: not reported
Plasma VL: 60% with <50 copies/mL
Injection drug use: not reported
Karnofsky Score (mean): 87
k.CPI-1189(Clifford et al.)36 Randomized, double-blind, placebo-controlled studyn = 64 Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. HAND: Any cognitive impairment Assess safety and tolerability of CPI-1189 in treating HIV-associated cognitive–motor impairment Not discussed. Whether or not the subjected completed the study on the original dose of medication. HAND: not reported 10 weeks
Ages: not specified Sex: 84% male
ART: stable regimen for ≥8 weeks, if on ART. Age (mean): 43.4 years
CD4 count: not specified Race/Ethnicity: 52% white
VL: not specified Education (mean): 14 years
Duration HIV+ (mean): 7.9 years
CD4 count (mean): 262 cells/mm3
CD4 nadir: not reportedLog10
Plasma VL (mean): 3.6 copies/mL
Injection drug use: not reported
Karnofsky Score (mean): 83
l.D-Ala1-peptide T-amide (DAPTA, or Peptide T)(Heseltine et al.)37 Randomized, double-blind, placebo-controlled studyn = 215 Cognitive dysfunction: ≥1.5 SD below norm on ≥2 tests, or ≥2.5 SD below mean on 1 test. HAND: Any cognitive dysfunction. Stratified on severity of impairment (severe, mild-moderate) Determine whether intranasal peptide T improves cognitive function in HAND Dose and route (intranasal) based on previous data from limited PK and Phase I studies 6-month change global neuropsychological z-score summarizing 23 measures HAND: 66% severe deficit 6 months
Severe dysfunction: ≥1.5 SD below norm on ≥2 tests, one of which was ≥2.5 SD below norm Ages: 18–60, stratified on range (18–39, 40–60) Sex: 95% male
ART: None within 4 weeks or any stable standardized regimen for ≥12 weeks. Stratified on use (yes, no) and length of use (never, ≤3 months ago, >3 months ago) Age: 57% 18–39 years
CD4 count: not specified, stratified on count (<200, 200–500, >500 cells/mm3) Race/Ethnicity: 82/5% white/black
VL: not specified Education (mean): 15 years
Duration HIV+ (mean): not reported
CD4 count (mean): 53% with ≤200 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Substance Abuse: 56% previous use
Karnofsky Score: not reported
l1.D-Ala1-peptide T-amide (DAPTA, or Peptide T)(Goodkin et al.)38 Retrospective substudy of above randomized, double-blind, placebo-controlled study27 n = 92 (for CSF studies), n = 57 (for peripheral studies) As above29 As above29 Examine if intranasal DAPTA is associated with a reduction in CSF and peripheral VL among a subgroup of participants enrolled in the study above37 As above29 6-month change in CSF and peripheral VL CSF VL Studiese: 6 months
HAND: 58% severe deficit
Sex: 98% male
Age (mean): 40 years
Race/Ethnicity: 85/4% white/black
Education (mean): 15.2 years
Duration HIV+: not reported
CD4 count: 45% with ≤200 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Substance Abuse: 61% previous use
Karnofsky Score: not reported
m.Lexipafant(Schifitto et al.)39 Randomized, double-blind, placebo-controlled study n = 30 Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. HAND: Any cognitive impairment. Assess the safety and tolerability, of lexipafant in HAND Not discussed Whether or not the subjected completed the study on the original dose of medication. HAND: Global impression: 7/50/37/7% normal/mild/moderate/severe impairment 10 weeks
Global impression of cognitive function assessed by neuro-psychologist, does not exclude abnormal NP test scores Ages: not specified Sex: 73% male
ART: stable regimen for ≥6 weeks Age (mean): 42.6 years
CD4 count: not specified Race/Ethnicity: 43% white
VL: not specified Education (mean): 13.4 years
Duration HIV+ (mean): 6.5 years
CD4 count (mean): 390 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Illicit drug use: none reported during trial
Karnofsky Score (mean): 81
n.OPC-14117(The Dana Consortium 1997)40 Randomized, double-blind, placebo-controlled studyn = 30 MSK staging HAND: Any cognitive impairment Assess the safety and tolerability of OPC-14117 Not discussed Whether or not the subjected completed the study on the original dose of medication. HAND: 53/47% ADC 0.5/1 12 weeks
Cognitive impairment: ≥1 SD below norm on ≥2 tests, or ≥2 SD below norm on 1 test. Ages: not specified Sex: 83% male
ART: stable regimen for ≥6 weeks Age (mean): 41.7 years
CD4 count: not specified Race/Ethnicity: 57/37% white/black
VL: not specified Education (mean): 13.5 years
Duration HIV+ (mean): 5.3 years
CD4 count (mean): 234 cells/mm3
CD4 nadir: not reported
Plasma VL: not reported
Illicit drug use: none reported during trial
Karnofsky Score (mean): 85

HAND, human immunodeficiency virus-associated neurocognitive disorder; MND, mild neurocognitive disorder; ART, antiretroviral therapy; VL, viral load; MSK, Memorial Sloan Kettering.

a

Uganda Neuropsych Test Battery Summary Measure: Grooved Pegboard dominant and nondominant hand, Color Trails 1 & 2, Symbol Digit Test, WHO-UCLA Verbal Learning test trial 5 total, WHO-UCLA Verbal Learning Test delayed recall, Digit Spans forwards and backwards.

b

NPZ8: Trail Making Test parts A and B, Grooved Pegboard Test with dominant and nondominant hand, CalCAP Choice and Sequential Reaction Test Time, Timed Gait Test, Symbol Digit Test.

c

NPZ6: Rey Auditory Verbal Learning (total number correct and delayed recall), Grooved Pegboard Test with dominant and non-dominant hand, CalCAP Choice and Sequential Reaction Time Test.

d

GDS (Global Deficit Score): A mean deficit score derived from multiple individual test deficit scores (based on T scores) of the following measures: Hopkins Verbal Learning Test-Revised, Brief Visuospatial Memory Test-Revised, Controlled Oral Word Association Test, semantic verbal fluency, Stroop color-Word Test, Train Making Test, Parts A and B, Wisconsin Card Sorting Test-64 Card Version, Halstead Category Test, Paced Auditory Serial Addition Test, Grooved Pegboard Test, the Digit Symboy, Symbol Search, and letter-Number Sequencing tests from the Wechsler Adult Intelligence Scale-Third Edition41.

e

Peripheral VL Studies had a slightly different covariate mix, but are not presented here for the sake of brevity.