HELD TO RANSOM-CMV TREATMENT IN SOUTH AFRICA REV IEW

Almost all humans are latently IgG-seropositive for the double-stranded DNA human herpesvirus 5 named cytomegalovirus (CMV). CMV is an AIDSdefining World Health Organization (WHO) stage 4 opportunistic infection for both adults and children, seen when the CD4 T-cell count falls below 100 cells/μl and as an immune reconstitution syndrome after starting highly active antiretroviral therapy (HAART).


Fig. 1. CMV Retinitis at baseline. Full-thickness retinal necrosis along the inferotemporal arcade with some haemorrhage. There is minimal vitritis and mild macular oedema (courtesy Dr Linda Visser, University of KwaZulu-Natal).
CMV of the neurological system. 6Encephalitis presents with headache, subacute personality changes, decreased concentration, and progressive dementia.

SOUTH AFRICAN SPECTRUM OF DISEASE
Most data for CMV in the developed world were established in the 1990s, before the HAART era.CMV-R was found in a third of AIDS patients, with a large resulting burden of blindness. 7In one pre-HAART Swiss study of 48 patients, median survival after CMV retinitis was 6 months. 8HAART improved survival markedly in AIDS CMV-R patients. 9 There is a paucity of CMV data in the developing world.CMV has been called the 'neglected disease of the AIDS pandemic' because of poor diagnostic and treatment capability. 1 In South Africa's pre-HAART era, 90 AIDS patients were treated for CMV-R at the University of Natal over 7 years, and the incidence was noted to increase with time.South Africa has both a high burden of HIV disease 12 and a large, expanding HAART programme. 13Many South African HIV-infected patients present for initiation of HAART when the CD4 count is less than 100 cells/µl, 14 and often the median is less than 50 cells/µl, 15 which makes them susceptible to CMV disease.The return to health and longevity that HAART confers 16 shapes a powerful argument to treat CMV efficiently and prevent its debilitating effects.

DIAGNOSTIC OPTIONS
A variety of testing options exist to identify active systemic CMV infection (Table I).Viral culture is traditionally accepted as the 'gold standard' method of detection. 17Simpler and more rapid options are now proving as or more effective. 18The pp65 antigen assay can provide very sensitive results in less than 6 hours, the main drawback being the need for immediate sample processing after retrieval in order to ensure test validity.Serological tests for the presence of IgM and IgG antibodies may have little diagnostic value in the immunocompromised patient.CMV DNA-PCR tests provide sensitive results that can reproducibly quantify CMV viral loads. 19In HIVinfected patients, both DNA-PCR and pp65 antigen assay have proven to be more predictive in detecting CMV than serology or viral culture. 20The CMV pp67 mRNA test is a promising new method used in research settings.

TREATMENT: THE URGENT NEED FOR VALGANCICLOVIR PRICE REDUCTION IN SA FOR CMV TREATMENT IN HIV PATIENTS
CMV treatment strategies (Table II) include systemic as well as local products, the latter for opthalmological indications.After completion of an induction phase, patients remain on maintenance therapy until immune recovery (CD4 >100 cells/µl).
Because southern African health facilities are poorly resourced, widespread use of intra-ocular ganciclovir (GCV) is not feasible. 1Specialist ophthalmological services are scarce in the state sector, and sometimes non-existent in rural areas.Intra-ocular GCV may not always be acceptable to patients, and is not without procedure-related adverse effects such as endophthalmitis. 10Most importantly, intra-ocular GCV does not prevent spread of CMV to the other eye, and completely fails to treat disseminated CMV. 1,10fortunately, the exorbitant cost of systemic CMV treatments is prohibitive in the state sector.Systemic GCV necessitates a 3-week stay in hospital for intravenous induction, followed by oral maintenance GCV. 21Lengthy intravenous induction is not always realistic in resource-poor settings and may place

PAEDIATRIC CMV TREATMENT AND PREVENTION IN PREGNANCY
Congenital CMV causes a broad range of neurodevelopmental deficits in both symptomatic and initially asymptomatic neonates, including microcephaly, chorioretinits and sensorineural hearing loss.
A 6-week course of intravenous ganciclovir has been shown to be effective in preventing hearing loss, improving weight gain and head circumference, and resolving hepatic dysfunction, hepatomegaly and retinitis.Ganciclovir toxicity, especially neutropenia, can however be life-threatening. 22sults of a small pharmacokinetic study show that oral valganciclovir at a dose of 16 mg/kg provided similar plasma levels of drug compared with 6 mg/kg intravenous ganciclovir, so it appears that valganciclovir is a promising option for treating neonatal and paediatric patients. 23rtical CMV transmission is trans-placental, and the rate is observed to be higher in HIV-1-infected mothers.Infants who are co-infected with HIV-1 and CMV are more likely to have rapid HIV disease progression. 24lganciclovir and ganciclovir are both considered potentially teratogenic from animal data, but there are no controlled studies in pregnant women.
A recent development in March 2009 is a CMV vaccine that may offer future public health benefits for pregnant women by eliminating congenital CMV. 25

HOW CAN VALGANCICLOVIR PRICE REDUCTION BE ACHIEVED IN SOUTH AFRICA?
Currently, the cost of CMV treatment makes it unaffordable to most.

Letters of concern on behalf of the
Transverse myelitis may occur.CMV is a recognised cause of acute inflammatory demyelinating polyradiculopathy (Guillain-Barré syndrome), the hallmarks of which are rapidly progressive ascending and often asymmetrical paraesthesiae, sensory loss and areflexia, as well as urinary retention, constipation and incontinence.The cerebrospinal fluid may demonstrate polymorphonucleocytosis and raised protein, and the diagnostic method of choice is polymerase chain reaction (PCR) testing of the cerebrospinal fluid for CMV DNA.

Fig. 2 .
Fig. 2. CMV retinitis after six intra-ocular ganciclovir injections.Note scarring in the area of previous necrosis.There is less vitritis, and the macular oedema has resolved.Haemorrhages may take months to resolve, and intraretinal gliosis can usually be seen late (courtesy Dr Linda Visser, University of KwaZulu-Natal).

TABLE I . CMV DIAGNOSTIC TESTS
tively for a 26-box order) (CHF = Swiss franc, 1 CHF = 7.47309 ZAR, exchange rate at 1 June 2009).NGO orders can be placed only at Roche Basle (sandra.torriani_cazzato@roche.com).The lead time is 3 months after receipt of firm order.Prices quoted are per Roche, May/June 2009.FBI = full blood count; AZT = zidovudine.