The results from this study support the clinical benefit of HAART for stavudine-based therapy in HIV+ individuals in Uganda. After the initiation of HAART, HIV+ individuals had improvement in their level of immune suppression with increased CD4 counts. HIV+ individuals had improvement in their overall functional performance as measured by the Karnofsky scale. HIV+ individuals also had improvements in their neurocognitive performance in tests of verbal memory, psychomotor and motor speed performance, executive functioning, and verbal fluency similar to the results of a prior pilot study in Uganda evaluating the effect of HAART on neurocognitive performance.10
The neuropsychological test improvement among HIV+ individuals is likely due to a combination of both HAART-associated improvements in immune suppression and neurocognitive function as well as practice effects. Compared with HIV− individuals, HIV+ individuals showed greater improvement in Color Trails 2, a test of executive functioning, suggesting that practice effects alone cannot account for the improvements seen in executive functioning. However, a ceiling effect for performance on this test, where the HIV− subjects could not improve significantly from baseline normal function, could have limited the learning effects relevant to the control group. Other cognitive domains, e.g., verbal memory, showed trends for greater improvement among HIV+ individuals compared with HIV− individuals. However, the sample size of the study may not have been large enough to detect a difference between the two groups. In addition, it is possible that some of the neurocognitive impairment among the HIV+ individuals at baseline may have been due to confounding factors other than HIV infection itself, and thus unlikely to improve with HAART.
The prevalence of neuropathy symptoms and signs at baseline in our study is similar to the prevalence of neuropathy symptoms and signs in Western countries among HIV+ patients with advanced immunosuppression,3–5
because the mean CD4 count of our HIV+ cohort was 129 cells. Stavudine-based HAART is also associated with some measurable neurologic morbidity. In Western countries, d-drug based HAART is rarely used now because of the risk of peripheral neuropathy. In our study in Uganda among HIV+ patients without peripheral neuropathy at baseline, 31% to 38% of these patients developed either symptoms or signs of neuropathy during the study. The onset of the symptomatic neuropathy experienced after starting therapy was prompt within the first 3 months of the trial, suggesting that stavudine may have been the cause of the neuropathy or stavudine decreased the threshold for developing an HIV-related neuropathy. The severity of these symptoms did not lead to HAART discontinuation in any of these patients. However, the study duration was only 6 months. At present, it is unclear whether a cumulative toxicity of stavudine over longer periods of treatment might result in a greater proportion affected or more severe neuropathy in those taking this therapy. Future studies of neuropathy should include a more extensive period of follow-up.
There are limitations to the study. The study was conducted among HIV+ patients from an urban setting in Kampala, Uganda, which is likely to be representative of the urban HIV+ community in Uganda. However, it may not necessarily reflect the HIV+ population in rural Uganda.
All study participants received a screening test for depression symptomatology, the Center for Epidemiologic Studies–Depression Scale (CES-D).21
At baseline, the mean CES-D score for the HIV+ group was 18.1 (SD 11.4). Thus, some patients may have had major depression. However, a psychiatrist on site evaluated any patient in which an active psychiatric condition was a concern.
HIV subtypes D and A are the predominant subtypes in Uganda, whereas subtype C is the predominant subtype in southern Africa. If HIV subtype has an effect on HIV neuropathogenesis, our results in Uganda may not necessarily reflect the HIV+ population throughout Africa.
HIV+ patients did not receive either neuroimaging or CSF examinations to rule out another CNS disease as the cause for an individual’s cognitive impairment. Other infectious diseases, such as tuberculosis, syphilis, or malaria, or malnutrition could have contributed to the cognitive impairment in our study participants. However, all HIV+ patients did receive a detailed neurologic history and examination (including an evaluation of fever, headache, neck stiffness, and focal abnormalities). Any HIV+ patient with a suspected CNS opportunistic infection or neoplasm was excluded from the study.
The neuropsychological tests that showed the largest improvement among the HIV+ patients were the tests that had the largest baseline Z score deficits. Thus, regression to the mean may have been a contributing factor for some of the neurocognitive improvement seen among the HIV+ patients.
HIV+ individuals demonstrated greater improvement in functional performance compared with HIV− individuals. However, the HIV− individuals had normal functional performance in general, so this group had little capacity for further improvement.
The cause of the neuropathy could not be fully determined due to the design of the study. A screening question for diabetes was included, and two HIV+ individuals reported a history of diabetes. Screening tests for other causes of neuropathy and electrophysiological studies were not available in Uganda. Ideally, a group of HIV+ individuals with the same inclusion criteria at study entry who were not on a stavudine-based regimen could have been evaluated, but this group of patients did not exist at the time of the study.
HAART is a lifesaving therapy for HIV+ patients with advanced immunosuppression in sub-Saharan Africa, and if a patient meets clinical criteria, HAART should be initiated without delay. If no other antiretroviral drug options are available, stavudine-based HAART can provide benefit with respect to immune system restoration and improvement in executive functioning in HIV+ individuals with neurocognitive impairment. However, this study provides data demonstrating that peripheral neurotoxicity is a significant problem from stavudine-based HAART, and if possible, alternative antiretroviral drug combinations should be provided. It is anticipated that future trends will have decreased use of stavudine-based therapies in resource limited countries. Additional resources to provide HAART regimens without stavudine would provide a great benefit by preventing a potential increase in the prevalence of painful peripheral neuropathy among millions of HIV+ individuals who will need HAART within the next several years in sub-Saharan Africa.