CMV retinitis: neglected disease of the AIDS pandemic

Cytomegalovirus (CMV) is a member of the herpes virus family that was a familiar cause of blindness and death in patients with advanced AIDS in Western countries in the 1980s and 1990s, when it occurred in roughly one-third of patients with AIDS.

Infection may lie dormant and activate once the immune response is weakened, making patients with advanced AIDS, with CD4 count below 50, most at-risk.

The near universal access to early treatment with antiretroviral therapy (ART) has made the disease clinically infrequent in the West.  But in developing countries, this is far from being the case, especially in South East Asia where observations suggest that the extent of the problem is similar to the pre-ART era in Europe or the United States.

CMV infection can present in the eye as CMV retinitis, leading to a slow but relentless destruction of the retina in three to six months, with profound and irreversible blindness occurring much more quickly; or it may be extra-ocular (in the central nervous system, gastrointestinal tract, or other organs) and lead to death.

What are the current prevalence rates of CMV retinitis?
The exact scale of the problem in developing countries is not known.  It is also difficult to extrapolate, because although HIV-prevalence figures are usually available, the numbers rarely are sub-divided into different CD4 count levels, so assessing CMV prevalence on the basis of most at-risk patients is often not possible.

For extra-ocular CMV, mortality is impossible to assign without resorting to autopsy, and is therefore often wrongly attributed to tuberculosis or "advanced HIV infection".

For CMV retinitis, it has been estimated that between 5 and 25% of HIV-positive patients in developing countries can be expected to develop this blinding disorder at one point during their illness.  Ophthalmology centres in Northern Thailand and Southern India have reported CMV retinitis prevalence in HIV patients at 33% and 17% respectively.  In Africa, the problem would appear to be less severe, however studies showing extremely short mean survival times between CMV diagnosis and death would suggest that under diagnosis is likely.

Below are the results of  "pilot studies" in regions where CMV had not yet been a documented problem.  These preliminary investigations give clear evidence that CMV retinitis is clinically substantial and must become part of the AIDS health policy agenda.

How is CMV retinitis detected?
The difficulty in diagnosing CMV retinitis is that the disease is often asymptomatic in its earlier stages, so limiting screening to symptomatic patients only is not reliable.  Even in a Cambodian survey specifically targeted to elicit symptoms of CMV retinitis, MSF found that 44% of patients subsequently detected through screening examination presented no symptoms.

Yet diagnosis of CMV retinitis, unlike extra-ocular CMV, is feasible. The "gold standard" technique involves retinal examination using an indirect ophthalmoscope on fully dilated pupils.  An indirect ophthalmoscope is designed to provide a stereoscopic image of the retina or vitreous of an eye from an inverted image produced by a lens.  It allows for better visualisation of any peripheral retinal disease.  Full dilation is critical because without a dilated pupil only a fraction of the retina can be examined.

The technique can easily be performed by a clinician after one month's training. There is no need for any laboratory or eye tests.  Diagnosis is highly specific and sensitive, and can be done in less than two minutes.

Systematic screening all at-risk patients (with CD4 counts under 50) must therefore become a fundamental part of HIV programmes.  Because CMV-related vision deterioration and blindness is usually irreversible, diagnosis must be brought down to primary health care level, in order to catch patients as early as possible.

How is CMV retinitis treated?
In Western countries in the pre-ART era, CMV retinitis was treated to ensure that patients with advanced AIDS did not go blind before they died.

Today, many HIV infected patients in developing countries including in East and South East Asia, have advanced AIDS before antiretroviral therapy begins.  Despite the ARVs, those that also have active CMV infection may go blind without treatment to target CMV.  This can have serious effects on the faith in HIV treatment amongst health staff and patients alike: in cases where loss of sight occurs without explanation after a patient starts on ART, patients may associate antiretroviral therapy with blindness.

Any medication to treat must be given in addition to antiretroviral therapy, until the immune system recovers sufficiently (to CD4 counts of at least 100) to keep CMV infection in check and make reactivation unlikely □ it is therefore a time bound, and not a chronic life-long treatment.

There are currently two effective treatment options in resource-poor settings, but both come with serious shortcomings.  The first is intravenous ganciclovir, which can be administered daily or twice daily as a treatment for the ocular CMV retinitis, as well as systemic (extra-ocular) CMV.  IV ganciclovir is cumbersome and costly, requiring twice daily infusions for two to three weeks, followed by once daily infusions for three months of until immunity is sufficiently restored (usually with the CD4 count above 100).

The second is intraocular injections of ganciclovir, which is currently considered the only viable option in resource-poor settings, despite the fact that in being a local treatment it entirely fails to address systemic CMV morbidity and mortality, or protect the other eye.  The need for repeated injections into a patient's eye makes this option both technically complex to administer,  and challenging to achieve good compliance, particularly when patients are asymptomatic.

Valganciclovir is an oral drug that can achieve equivalent blood levels as intravenous ganciclovir.  Coming in a pill form means that it is patient-friendly.  It addresses systemic disease. It is also effective for both initial induction treatment and subsequent maintenance treatment.  All these factors combine to make valganciclovir the only option simple enough to make integration of CMV treatment into HIV programmes feasible.

Why is valganciclovir not widely used for CMV retinitis?
One key issue is the price of the drug, which remains exorbitantly expensive.  Currently, the price for a treatment course is US$ 10,273, or ? 6,930.  Roche of Basel, Switzerland holds patents in most countries around the world, and is currently the only producer of this drug.

Following negotiations between MSF and Roche, the manufacturer of valganciclovir, in early 2007, MSF was offered a discounted price of US$ 1,899 or ? 1,281.  This remains extremely expensive.  In addition, the offer has severe limitations as it applies only to least-developed countries and sub-Saharan Africa, so programmes in China or Thailand are excluded from the deal. This is a serious problem in that both countries are now diagnosing patients, but have virtually no access to valganciclovir. The offer is also limited to NGOs only, making uptake of CMV treatment through the governmental public health system impossible.

The reason for Roche's reluctance to lower the price is likely due to the fact that the drug is marketed as a prophylaxis for CMV in transplant patients in wealthy and middle-income countries. Roche is targeting a small but lucrative market, and protecting its position through patent monopolies.

A patent on valganciclovir was granted in India in June 2007. This prevented the ongoing development of generic products, leaving Roche as the sole source for the drug.

What is the current response to CMV retinitis?
The vicious circle of little diagnosis-poor treatment options-little pressure to improve either diagnosis or treatment options is perpetuated by the absence of CMV retinitis from current and pending guidelines issued by the World Health Organization (WHO) for the management of HIV in resource-poor settings. In addition, CMV retinitis is absent from WHO's "Vision 2020" programme on the use of ophthalmologic resources until year 2020.

Yet the shortfall in ophthalmologists, (who tend to be in cities, far from where many of the most vulnerable patients are) means that diagnosis and treatment for CMV retinitis must be firmly placed within AIDS programmes, and at the primary health care level, just like all other important opportunistic infections, to ensure early diagnosis.

WHO must develop a simple training package for diagnosis and treatment of CMV retinitis at the primary health care level, as a first step to moving towards a systematic diagnosis of all at-risk patients through indirect ophthalmoscopy and systematic treatment through affordable oral valganciclovir.

MSF involvement in PLoS Medicine article
MSF programmes in Cambodia, South Africa, Lesotho, China, Thailand, and Myanmar, have collaborated in this work, beginning in 2004, under the initiative of Dr. David Heiden, of SEVA Foundation.

Currently there are a range of different responses depending on the cost of valganciclovir in the above countries. In Thailand for example, a country excluded from the discounted price, diagnosis is done by general practitioners using indirect ophthalmoscopy at the community hospital and health station level. Patients are then referred to specialist centres for intra-ocular ganciclovir if indicated. MSF is currently collaborating with the Ministry of Public Health on disseminating this care model to other districts. In China MSF pays the full price for oral valganciclovir, which is higher than the price of a Chinese economy car.