A frail 68-year-old woman of European ancestry presented to the emergency department with partial seizures of her left hand and mild left hemiparesis. Magnetic resonance imaging (MRI) scans of the brain revealed a non-enhancing lesion in the right precentral gyrus that was thought to represent infarction (Box, A and B).
After surgery, the patient began highly active antiretroviral therapy (HAART) with a regimen comprising Trizivir (abacavir, lamivudine and zidovudine) and ritonavir-boosted indinavir. She experienced symptomatic improvement, weight gain and reduced partial seizures within a few weeks. The plasma HIV viral load was undetectable within 8 weeks of commencing HAART and a repeat MRI scan at that time confirmed a significant reduction in size of the cerebral lesion (Box, C).
Our patient presented with PML as her AIDS-defining illness with synchronous colonic neoplasms on a background of multiple medical conditions. With hindsight, these conditions were all linked to immunosuppression due to unrecognised HIV infection. It is likely that prolonged HIV replication in sanctuary sites, such as the gastrointestinal tract and brain, were responsible for her small bowel, colonic and central nervous system (CNS) disease manifestations. Impaired immune dysregulation may have contributed to the aggressiveness of the tumour behaviour.
PML is a demyelinating disease of the CNS caused by JCV, a human polyomavirus. The condition generally occurs in the setting of prolonged immunosuppression among individuals with decreased cell-mediated immunity, such as HIV infection.1 In the pre-HAART era, the prognosis for PML was very poor, with median survival times no greater than 6 months.2 With the advent of HAART, the survival time has improved to 15 months or more, but mortality rates can still be as high as 30% to 50%.3 PML has also been documented among patients who receive certain immunosuppressive drugs, such as fludarabine, rituximab, corticosteroids,2 and shortly after the introduction of HAART as a form of immune-reconstitution inflammatory syndrome.4 In HIV infection, HAART is the only therapeutic option for PML, but the efficacy of these agents in controlling JCV replication in the CNS is variable and clinical response is not uniform. Antiretroviral agents with good CNS penetration have been used to optimise therapy for patients with PML.3
Previous studies have suggested the mean time to AIDS diagnosis from HIV acquisition after transfusion was 7 years,5 although a cohort of “non-progressors” who acquired a variant strain of HIV containing the nef gene deletion has been well documented.6 Our patient had delayed progression to AIDS, even in the absence of HAART, a clinical pattern that has been linked to several other genetic factors, including chemokine coreceptor type 5 (CCR5) status.7, 8 CCR5 is a coreceptor required for HIV to enter T cells and macrophages. Homozygosity for the Δ32 gene deletion in the CCR5 gene (CCR5-Δ32) is associated with resistance to HIV infection (although people can still be infected with T-tropic strains of the virus, which use the CXC chemokine receptor type 4 for cell entry), whereas heterozygosity confers delayed progression to disease. Our patient was confirmed as being heterozygous for CCR5-Δ32. In the United States, the frequency of the allele is 11% among white people and 1.7% among black people.8 Targeting the CCR5 receptor to interrupt HIV transmission offers new therapeutic possibilities. Maraviroc, a CCR5 inhibitor, has been introduced with success when used as part of a HAART regimen for patients with R5 (M-tropic) virus.9 Transplantation of stem cells from a donor homozygous for CCR5-Δ32 to a patient with acute myeloid leukaemia and HIV infection resulted in continued virological suppression after transplantation in the transplant recipient and discontinuation of HAART.10
One approach to help identify individuals who are unaware that they have HIV infection is the “opt-out” HIV testing strategy proposed by the US Centers for Disease Control and Prevention in 2006.11 All people aged 13–64 years in health care settings would have routine HIV testing. Importantly, pretest counselling and signed consent would not be required, and the test would be performed unless the patient declined. Patients with known risks for HIV infection should be tested annually.11 This testing strategy would allow undiagnosed patients earlier access to medical care with an anticipated reduction in HIV transmission and infection related morbidity and mortality.12
The World Health Organization endorsed these recommendations in 2007, expanding the scope of uptake to the developing world.13 Drawbacks to this approach include concerns about stigmatisation and discrimination of individuals with HIV,14 and increased cost implications15 for health authorities from increased test numbers, including confirmatory immunoblot assays, and a requirement for more expertise to interpret true and indeterminate results.
We thank Dr Janice Brewer, Senior Pathologist from the Department of Anatomical Pathology at Royal North Shore Hospital, and Dr Michael Buckland, Honorary Associate of Pathology at the University of Sydney based at the Department of Neuropathology, Royal Prince Alfred Hospital for providing expert histopathological assessment.
No relevant disclosures.