Article one: Diagnosis and treatment of CMV retinitis in resource-limited settings achievable and a must, says MSF

By Michael Carter

The diagnosis and treatment of CMV retinitis in resource-poor countries is realistic, but is being over-looked in current HIV treatment scale-up plans, according to investigators from Medecins Sans Frontieres (MSF), writing in the December edition of PLoS Medicine. The article is freely available online here

Cytomegalovirus (CMV) is a member of the herpes virus family and was a frequent cause of blindness in individuals with advanced HIV disease in western countries before effective antiretroviral therapy became available.

Since potent anti-HIV treatment became available the incidence of CMV retinitis in countries like the UK has become rare. Furthermore, in industrialised countries there is now a well-established protocol for the diagnosis and treatment of CMV retinitis that includes retinal examinations for patients with low CD4 cell counts and treatment with effective anti-CMV drugs, such as ganciclovir, with concurrent antiretroviral therapy.

But in resource-poor settings CMV retinitis is a neglected disease, being under-diagnosed and under-treated. Indeed the diagnosis and management of the disease are absent from WHO HIV treatment guidelines, nor is the condition mentioned in the WHO “Vision 2020” programme.

It is uncertain how many HIV-positive patients in resource-limited settings are affected by CMV retinitis. Therefore investigators from MSF looked at the prevalence of the condition in patients receiving care from their HIV projects in Cambodia, South Africa, Lesotho, Myanmar, Thailand and China. Between 2% and 32% of patients receiving HIV care from MSF were found to have the condition.

The gold standard for diagnosis of CMV retinitis is examination of the retina through a dilated pupil by a skilled clinician using an opthalmoscope.

CMV retinitis is characterised by dense whitening of the retina. Without treatment, CMV retinitis destroys the entire retina within three to six months, causing permanent blindness.

Common symptoms of CMV retinitis include floaters or blurred vision. But limiting retinal examinations only to patients who complain of vision problems is not reliable, and in resource-rich countries it is recommended that all patients with a CD4 cell count of 50 cells/mm³ (when CMV retinitis becomes a real risk) should have regular retinal examinations.

“We believe that systematic screening examination of the retina should be a fundamental requirement of HIV-related care in resource-poor settings”, write the investigators. They note, “in our recent work in Myanmar 31% of patients diagnosed with CMV retinitis had no symptoms”.
Successful treatment of CMV retinitis requires the use of both CMV-specific medication and antiretrovirals.

Ganciclovir is the current gold standard CMV therapy. The drug can be used as a systemic CMV therapy or can be injected directly into the eye as a local treatment for CMV retinitis. Valganciclovir achieves the same blood levels as ganciclovir and has the advantage of being an oral treatment.

But cost considerations mean that the direct injection of ganciclovir into the eye is the only treatment for CMV retinitis that is available in resource-limited settings. Such therapy costs 57 US cents per week compared to $57 per day for oral valganciclovir.

Moreover access to ganciclovir eye injections in resource-limited settings is very limited, particularly as clinicians who are qualified to administer them are in short supply. Furthermore, the injections are frightening to patients and may deter asymptomatic individuals, who have the most to gain from therapy, from accessing treatment.

“We believe that systemic treatment with oral valganciclovir should be used routinely as the primary treatment strategy because (1) systemic treatment of CMV retinitis reduces extraocular disease; (2) systemic treatment reduces mortality; and (3) with only local treatment there is a 22% - 33% incidence of new CMV retinitis in the untreated eye”, write the investigators, “intraocular ganciclovir as the primary treatment strategy is simply not medically adequate.”

The costs of failing to treat CMV retinitis are considerable, causing blindness, resulting in loss of employment, and ultimately death. Expanding HIV treatment programmes are likely to mean that more patients with advanced HIV disease come forward for diagnosis and therapy. Many of these patients will be at risk of CMV retinitis and failure to treat the illness and resulting blindness will, the investigators believe, cause of “loss of faith in HIV treatment…and in the worst case scenario…may lead to reluctance to start taking this life-saving treatment.”

Two specific recommendations are made by the investigators. Firstly, diagnostic capacity should be expanded, with HIV treatment programmes designating a clinician to be trained to offer retinal examinations. A sturdy and portable opthalmoscope costs a little over $1000 and has been successfully field-tested in South Africa by MSF. Secondly, valganciclovir must be made available and affordable.

“Ongoing CMV-related mortality should no longer go unrecognised or be accepted as part of advanced HIV mortality. Patients should not be left vulnerable to blindness while clinicians are in the process of treating and controlling underlying infection with HIV”, conclude the investigators.

Reference
Heiden D et al. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Medicine 4 (12) e334, 2007.

Article two: Starting antiretroviral therapy early at higher CD4 cell counts improves short term treatment outcomes in resource-poor countries

By Tom Egwang

HIV-positive adult Cote D’Ivoirians who started antiretroviral therapy before CD4 counts fell below 350 cells/mm³ experienced significantly improved treatment outcomes with fewer deaths when compared to those who started treatment later, according to the findings of a paper published in the November 30^th edition of AIDS.

International and national efforts across sub-Saharan Africa are on-going to provide universal antiretroviral therapy access to millions of HIV-positive patients. At present, the treatment guidelines recommend starting anti-HIV treatment when CD4 counts are less than 200 cells/mm³ in HIV-infected patients. However, some of these patients already have considerable immunosuppression and experience HIV disease progression or even death within a few months of starting antiretrovirals.

The incidence of deaths occurring during the early months following antiretroviral initiation is higher in African patients than that in patients from industrialized countries. With increasing access to antiretroviral therapy soon becoming a reality in Africa, it is important to institute interventions which prevent mortality in patients in resource-poor settings who start anti-HIV therapy when immunosuppression has advanced.

There is a paucity of information about risk factors which account for the increased incidence of mortality and morbidity within the first months following the initiation of anti-HIV treatment. A team of French and Cote D’Ivoirian researchers have addressed this issue in a cohort of HIV-infected adults in Cote D’Ivoire. The study was part of a bigger study of structured treatment interruption strategies in HIV-infected subjects in Abidjan.

This part of the study focused on the initiation of anti-HIV therapy in consenting patients 18n years old or older with no history of antiretroviral use, CD4 counts between 150 and 350 cells/mm³ or CD4 percentage between 12.5 and 20.0 %. All patients were given prophylaxis with cotrimoxazole.

All patients started continuous ART with either AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and efavirenz (Sustiva) or efavirenz or AZT, 3TC and indinavir/ritonavir. The patients were followed for eight months before being randomised for the second phase of the study. Patients in the treatment initiation phase therefore had CD4 cell counts which were higher than the recommended threshold for starting antiretroviral therapy.

The incidence of severe morbidity was monitored during the first months of treatment. Severe morbidity was defined as all World Health Organization (WHO) stage three or four four-defining morbidity events other than oral candidiasis. Virological success during the first months of anti-HIV treatment was defined as the first time when a viral load was undetectable. Immunological response was defined as the first time that there was a gain in CD4 cell counts of at least 50 cells/mm³ from baseline.

Trends for incidence of morbidity and death over time and the association of virological and immunological outcomes and other variables with severe morbidity and with death were analysed using statistical models.

Out of 840 adults enrolled in the trial, 48 were excluded from the analyses for various reasons. Out of the 792 patients who remained in the analyses, 71 % had a CD4 cell count of more than 200 cells/mm³ and 64 % were at WHO stage 1 or 2, indicating no or symptoms of HIV infection or very mild symptoms. This cohort started ART with a median CD4 cell count of 252 cells/mm³ and were followed for a median of eight months.

In patients with pre-ART CD4 cell count < 200, at 200–350 and >350 cells/mm³, the incidence of mortality was 5.0, 1.7 and 0.0 /100 person-years, and incidence of severe morbidity was 13.3, 9.5 and 7.9/100 person-years, respectively.

The most frequent diseases were invasive bacterial diseases (32/65 episodes, 49%) and tuberculosis (TB, 5/65 episodes, 38%). The first episode of TB occurred when the median last CD4 count was 235 cells/mm³ and the median time since initiation of antiretroviral therapy was 3.7 months.

The overall incidence of mortality during the first, second, and third quarter following ART initiation was 3.1, 1.0, and 1.5/100 person-years, respectively. The overall incidence of severe morbidity during the same periods was 16.6, 10.2, and 6.6/100 person-years, respectively.

Patients who experienced severe illness had higher risks of mortality, virological failure and immunological failure. The baseline risk factors for mortality and/or severe morbidity were high viral load, advanced clinical stage, past history of TB, low body mass index (BMI), low haemoglobin and low CD4 cell count. During follow-up, low CD4 cell count and persistently detectable viral load were risk factors.

Treatment guidelines in industrialised countries are already being revised to recommend initiation of anti-HIV treatment when the CD4 cell count falls below 350 cells/mm³, and the findings from Cote d'Ivoire are likely to raise calls for earlier treatment in resource-limited settings.

Reference
Moh R et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa. AIDS 21:2483–2491, 2007.

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HIV prevention with people living with HIV – A guide for NGOs and service providers

In the context of expanding provision of antiretroviral (ARV) treatment which is bringing improved health and new hope to many people living with HIV; ‘Positive prevention’ aims to provide a starting point from which NGOs and HIV service providers can support HIV positive people to lead full and healthy lives.

This guide is intended as a resource to help NGOs and HIV service providers working across the spectrum of HIV prevention, treatment, care and support services to take steps towards integrating HIV prevention for, by and with people living with HIV.

‘Positive prevention’ has been developed by Alliance HIV prevention programmes, as well as programming and policy staff of other organisations that are developing strategies and initiatives for HIV prevention for people living with HIV.

The guide does not intend to discuss or review all HIV prevention strategies and focuses largely on the sexual transmission of HIV.

Who is this publication for?
It is primarily intneded for NGOs and HIV service providers, but it will also be of use to individuals living with HIV and their partners.

How can you get a copy of this publication?
You can download a PDF or order a printed copy from the Alliance website