Cytomegalovirus is a multi-systemic infection reactivated in the immunocompromised. Diagnosis and treatment are prohibitively costly in sub-Saharan Africa, and efforts need to be made for their price reduction to support the expanding highly active antiretroviral treatment programme in the region

Ashford, G

Cescon, A

Cullen, C

Laher, F

Lazarus, E

Puren, A

Visser, L

English

AJOL - African Journals Online

T H E  S O U T H E R N  A F R I C A N  J O U R NA L  O F  H I V  M E D I C I N E                                                               A P R I L   2 0 1 0Almost all humans are latently IgG-seropositive for the double-stranded DNA human herpesvirus 5 named cytomegalovirus (CMV). CMV is an AIDS-defining 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).1 CLINICAL MANIFESTATIONSActive CMV disease may present multi-systemically, with significant morbidity and mortality. Organ sys-tem manifestations include:CMV retinitis (CMV-R). This is a visual emergency usually presenting with blurred vision, floaters, black spots, flashing lights, distortions, redness and photo-phobia, but sometimes asymptomatic. WHO clini-cal diagnosis guidelines for CMV-R include dilated pupil indirect fundoscopic identification of ‘discrete patches of retinal whitening with distinct borders, spreading centrifugally, often following blood ves-sels, associated with retinal vasculitis, haemorrhage and necrosis’.2 Figs 1 and 2 show CMV-R before and after local treatment, respectively. This fundoscopic picture is known as the ‘pizza pie’ appearance. CMV-R may result in blindness.3 CMV of the gastro-intestinal tract. Colitis is symp-tomatic as chronic watery diarrhoea that may become bloody, and oesophagitis symptomatic as dysphagia, anorexia and weight loss. Hepatitis may occur, and there are reports of acalculous cholecystitis.CMV adrenalitis. Adrenal insufficiency may manifest as postural hypotension, fatigue, hyponatraemia, hyperkalaemia and acidosis. It has a high mortality rate.4CMV pneumonitis. Manifestations are tachypnoea, hypoxia and dry cough, which are commonly misdi-agnosed as Pneumocystis jirovecii pneumonia.5HELD TO RANSOM - CMV TREATMENT IN SOUTH AFRICAREV IEWFatima Laher1, MB BCh, Dip HIV Man (SA) Gail Ashford 2, FCFP, Dip HIV Man (SA), DMH (SA) Angela Cescon3, BSc/BPHEClaire Cullen4, MB BChErica Lazarus1, MB BCh, Dip HIV Man (SA)Adrian Puren5, MB BCh PhDLinda Visser6, FCOphth1Perinatal HIV Research Unit, Soweto, Johannesburg2Donald Gordon Medical Centre, Parktown, Johannesburg3Faculty of Health Sciences, Simon Fraser University, Canada4Department of Ophthalmology, University of Limpopo and Dr George Mukhari Hospital, Limpopo Province5National Institute for Communicable Diseases, Sandringham, Johannesburg6Department of Ophthalmology, University of KwaZulu-Natal, Durban31Cytomegalovirus is a multi-systemic infection reactivated in the immunocompromised. Diagnosis and treat-ment are prohibitively costly in sub-Saharan Africa, and efforts need to be made for their price reduction to support the expanding highly active antiretroviral treatment programme in the region.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).A PR I L   2 0 1 0                                                                 T H E  S O U T H E R N  A F R I C A N  J O U R NA L  O F  H I V  M E D I C I N E CMV of the neurological system.6 Encephalitis pres-ents with headache, subacute personality changes, decreased concentration, and progressive dementia. Transverse myelitis may occur. CMV is a recognised cause of acute inflammatory demyelinating polyra-diculopathy (Guillain-Barré syndrome), the hallmarks of which are rapidly progressive ascending and often asymmetrical paraesthesiae, sensory loss and areflex-ia, as well as urinary retention, constipation and in-continence. The cerebrospinal fluid may demonstrate polymorphonucleocytosis and raised protein, and the diagnostic method of choice is polymerase chain re-action (PCR) testing of the cerebrospinal fluid for CMV DNA.SOUTH AFRICAN SPECTRUM OF DISEASEMost 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.7 In one pre-HAART Swiss study of 48 patients, median survival after CMV retinitis was 6 months.8 HAART improved survival markedly in AIDS CMV-R patients.9There 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.10 A cross-sectional study screening all HIV-infected patients with CD4 counts <50 cells/µl in Khayelitsha, South Africa, diagnosed CMV-R in 2% of these patients using dilated pupil indirect ophthalmoscopy.1 In a South African autopsy study of 47 HIV-infected cadavers where the clinician-attributed cause of death had been tuberculosis, CMV pneumonitis was proven in 15% and 66% tested positive for CMV-DNA.11South Africa has both a high burden of HIV disease12 and a large, expanding HAART programme.13 Many South African HIV-infected patients present for ini-tiation 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 dis-ease. The return to health and longevity that HAART confers16 shapes a powerful argument to treat CMV efficiently and prevent its debilitating effects.DIAGNOSTIC OPTIONSA variety of testing options exist to identify active systemic CMV infection (Table I). Viral culture is tra-ditionally accepted as the ‘gold standard’ method of detection.17 Simpler and more rapid options are now proving as or more effective.18 The pp65 antigen as-say can provide very sensitive results in less than 6 hours, the main drawback being the need for im-mediate sample processing after retrieval in order to ensure test validity. Serological tests for the pres-ence of IgM and IgG antibodies may have little di-agnostic value in the immunocompromised patient. CMV DNA-PCR tests provide sensitive results that can reproducibly quantify CMV viral loads.19 In HIV-infected patients, both DNA-PCR and pp65 antigen assay have proven to be more predictive in detect-ing CMV than serology or viral culture.20 The 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 PATIENTSCMV treatment strategies (Table II) include systemic as well as local products, the latter for opthalmo-logical 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.1 Specialist 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 with-out procedure-related adverse effects such as end- ophthalmitis.10 Most importantly, intra-ocular GCV does not prevent spread of CMV to the other eye, and completely fails to treat disseminated CMV.1,10Unfortunately, the exorbitant cost of systemic CMV treatments is prohibitive in the state sector. Systemic GCV necessitates a 3-week stay in hospital for in-travenous induction, followed by oral maintenance GCV.21 Lengthy intravenous induction is not always realistic in resource-poor settings and may place 32 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).32T H E  S O U T H E R N  A F R I C A N  J O U R NA L  O F  H I V  M E D I C I N E                                                               A P R I L   2 0 1 0Test Tube/transport Samples Volume required Turnaround time Price estimate (2009)pvt = estimated prices courtesy Toga Laboratories; state = estimated prices courtesy NHLS/NICD.TABLE I. CMV DIAGNOSTIC TESTSCMV viral culture (shell vial)CMV pp65 antigen (IFA)CMV IgG and IgMQualitative CMV DNA-PCRQuantitative CMV DNA-PCR (i.e. CMV viral load)No preservative Send on ice to ar-rive at lab and be processed within 24 hoursEDTA, room tem-perature, must be received at NICD before 14h00 same day as col-lectionYellow-topEDTAEDTAUrine, CSF aspirate, breastmilkBlood not an ideal sampleWhole blood  Result may be impossible if patient neutropenicBlood (serum)Any sample includ-ing blood, CSF, etc.Whole blood        1 ml        5 ml2 - 7 d (state), 3 - 28 d (pvt)1 - 3 d1 d1 d1 dR82 (state),R97.11 (pvt)R171 (state),R182.97 (pvt)IgG R104.85 (pvt),IgM R113.76 (pvt)R607.14 (pvt)R1 214.18 (pvt)Drug  Dose  Price estimates across sectors  Safety   Private State NGOValganciclovir  (Valcyte;  Roche) 450 mg per tablet, 60 tablets per bottleNo generics cur-rently available in South Africa Ganciclovir (Cymevene; Roche)Inj.: 500 mg in 10 ml vials ×5Caps: 250 mg (84), 500 mg (90) No generics cur-rently available in South Africa Initiation phaseMaintenance phaseInduction phase: intravenousMaintenance phase: oralLocal treatment for CMV retinitis900 mg bd po with meals × 21 days900 mg/d po with meals until HAART restores CD4 count >100 cells/µl5 mg/kg IV bd × 21 days1 g tds poR24 719.87for 21 daysR17 657.05 per monthR2 558.24  for 5 vialsR19 479.32 for 21 daysR13 913.85 per monthR1 789.65 for 5 vialsSpecially imprinted price-reduced boxes can be ordered by NGOs from Roche Swit-zerland* N/ADoubles ddI levelsMonitor FBC 2 - 3 × week Discontinue if neutrophils <0.5 ×109/l or plate-lets <25×109/l.Adjust doses in renal failureBeware pancy-topenia Monitor FBC every 2 days Reduce dose by 30 - 50% if neutrophils 0.5 - 0.8×109/l.Discontinue if neutrophils <0.5 ×109/l.Cautious use with AZT or ddI: similar toxicities Oral ganciclovir is not available in South AfricaSuggest maintenance with valganciclovirIn a recumbent patient, 2 mg of a 25 mg/ml ganciclovir solution in normal saline is injected with a 1 ml syringe and 30G needle, 4 mm behind the limbus of the eye superiorly with the patient looking down. Patients are given intravitreal ganciclovir injections twice a week for the first 2 weeks, then weekly until immune recovery or retinitis quiescence9*Minimum order of CHF 10 000. Each 60-tab box of 450 mg tablets costs CHF 500, plus freight and insurance changes apply (estimated CHF 177.40 + 40.20 respec-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.TABLE II. CMV TREATMENT IN ADULTS33A PR I L   2 0 1 0                                                                 T H E  S O U T H E R N  A F R I C A N  J O U R NA L  O F  H I V  M E D I C I N E immune-compromised patients at risk of contracting nosocomial illnesses.The benefits of valganciclovir are evident: it is taken orally, easy to administer in resource-poor settings, well tolerated, and efficacious in both induction and maintenance phases of treatment.21 Its cost currently prevents its use in South African CMV AIDS patients.Second-line intravenous treatment options such as foscarnet and cidofovir are avoided because of neph-ro-toxicity.PAEDIATRIC CMV TREATMENT AND PREVENTION IN PREGNANCYCongenital CMV causes a broad range of neurodevel-opmental deficits in both symptomatic and initially asymptomatic neonates, including microcephaly, cho-rioretinits and sensorineural hearing loss.A 6-week course of intravenous ganciclovir has been shown to be effective in preventing hearing loss, im-proving weight gain and head circumference, and resolving hepatic dysfunction, hepatomegaly and re-tinitis. Ganciclovir toxicity, especially neutropenia, can however be life-threatening.22Results 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 valganci-clovir is a promising option for treating neonatal and paediatric patients.23Vertical CMV transmission is trans-placental, and the rate is observed to be higher in HIV-1-infected moth-ers. Infants who are co-infected with HIV-1 and CMV are more likely to have rapid HIV disease progres-sion.24Valganciclovir and ganciclovir are both considered po-tentially teratogenic from animal data, but there are no controlled studies in pregnant women.A recent development in March 2009 is a CMV vac-cine that may offer future public health benefits for pregnant women by eliminating congenital CMV.25HOW CAN VALGANCICLOVIR PRICE REDUCTION BE ACHIEVED IN SOUTH AFRICA?Currently, the cost of CMV treatment makes it unaf-fordable to most.Letters of concern on behalf of the South African HIV Clinicians Society have been sent to Roche urging price reduction of CMV treatments in the sub-Saharan Af-rican region. Various organisations internationally are lobbying for price reduction, including Médecins Sans Frontières, Universities Allied for Essential Medicines and the Clinton HIV/AIDS Foundation.Valganciclovir for CMV treatment in AIDS patients must be placed on our state tender request list. Cur-rently it is available through state discretionary funds to transplant patients only. Government should con-sider compulsory licensing for price-slashed generic production of valganciclovir for the state sector.REFERENCES  1.  Heiden D, Ford N, Wilson D, et al. Cytomegalovirus retinitis: The neglected disease of the AIDS pandemic. PLoS Med 2007; 4(12): 1845-1851.  2.  World Health Organization. Revised WHO Clinical Staging and Immunological Classification of HIV/AIDS and Case Definitions of HIV and Related Conditions. Geneva: WHO, 2006.  3.  Jacobson MA, Stanley H, Holtzer C, et al. Natural history and outcome of new AIDS-related cytomegalovirus retinitis diagnosed in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 30: 231-233.  4.  Eddleston M, Peacock M, Juniper M, et al. Severe cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 1997; 24: 52-56.  5.  Baughman RP. Cytomegalovirus: The monster in the closet? Am J Respir Crit Care Med 1997; 156(1): 1-2.  6.  McCutchan JA. Cytomegalovirus infections of the nervous system in patients with AIDS. Clin Infect Dis 1995; 20: 747-754.  7.  Holbrook JT, Jabs DA, Weinberg DV, Lewis RA, et al. Visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. Arch Ophthalmol 2003; 121: 99-107.  8.  Olmari M, Gabriel V, Sansonetti A, et al. Long-term visual outcome in CMV retinitis. Presented at the Xth International Conference on AIDS, Yokohama, Japan, 7-12 August 1994 (abstract no. PB0517).   9.  Gross JG, Bozzette SA, Mathews WC, et al. Longitudinal study of cytomegalovirus retinitis in acquired immune deficiency syndrome. Ophthalmology 1990; 97(5): 681-686. 10.  Visser L. Managing CMV retinitis in the developing world. Comm Eye Health 2003; 16(47): 38-39.11.  Martinson NA, Karstaedt A, Venter WD, et al. Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. AIDS 2007; 21(15): 2043-2050.12.  National Department of Health, South Africa. Report: The National HIV and Syphilis Prevalence Survey South Africa 2007. http://data.unaids.org/pub/Report/2008/20080904_southafrica_anc_2008_en.pdf (accessed 7 May 2009).13.  National Department of Health, South Africa. HIV and AIDS and STI Strategic Plan for South Africa for 2007-2011, 2007. www.doh.gov.za/docs/misc/stratplan/2007-2011/part1.pdf (accessed 7 August 2009).14.  Keiser O, Orrell C, Egger M, et al. Public-health and individual approaches to antiretroviral therapy: Township South Africa and Switzerland compared. PLoS Med 2008; 5(7): e148. doi:10.1371/journal.pmed.0050148.15.  Coetzee D, Hildebrand K, Boulle A, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18(6): 887-895.16.  Lima VD, Hogg RS, Harrigan PR, et al. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS 2007; 21(6): 685-692.17.  Müller LV, Hampl W, Hinz J, et al. High variability between results of different in-house tests for cytomegalovirus (CMV) monitoring and a standardized quantitative plasma CMV PCR assay. J Clin Microbiol 2002; 40(6): 2285-2287.18.  Mocarski ES, Shenk T, Pass RF. Cytomegaloviruses. In: Knipe DM, Howley PM, Griffin DE, eds. Fields Virology. 5th ed, Philadelphia: Lippincott Williams & Wilkins, 2007: 2701-2772.19.  Boeckh M, Boivin G. Quantitation of cytomegalovirus: methodologic aspects and clinical applications. Clin Microbiol Rev 1998; 11(3): 533-554.20.  Dodt KK, Jacobsen PH, Hofmann B, et al. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 1997; 11: F21-F28.21.  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Held to ransom - CMV treatment in South Africa

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Held to ransom - CMV treatment in South Africa

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