WHO recommends earlier treatment and phase-out of d4T

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Everyone diagnosed with HIV infection should start treatment when their CD4 count falls below 350 cells/mm3, the World Health Organization announced in new recommendations published today.

The recommendation replaces previous guidelines for low and middle-income countries, which recommended treatment for people with advanced symptoms of HIV disease, or a CD4 count below 200 without symptoms.

The new guidance also recommends antiretroviral treatment with an efavirenz-based regimen for everyone with TB regardless of CD4 count, with antiretroviral therapy to be initiated soon after TB treatment.

Glossary

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

low income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. While the majority of the approximately 30 countries that are ranked as low income are in sub-Saharan Africa, many African countries including Kenya, Nigeria, South Africa and Zambia are in the middle-income brackets. 

first-line therapy

The regimen used when starting treatment for the first time.

fixed-dose combination (FDC)

Two or more drugs contained in a single dosage form, such as a capsule or tablet. By reducing the number of pills a person must take each day, fixed-dose combination drugs may help improve adherence.

capacity

In discussions of consent for medical treatment, the ability of a person to make a decision for themselves and understand its implications. Young children, people who are unconscious and some people with mental health problems may lack capacity. In the context of health services, the staff and resources that are available for patient care.

People with HIV and hepatitis B co-infection who have hepatitis B infection that requires treatment should also receive antiretroviral treatment with a regimen containing tenofovir and either 3TC or FTC, regardless of CD4 count.

The new guidance aims to bring treatment practice in low and middle-income countries into line with recommendations in Europe, North America and Australia, where earlier treatment has been the norm for several years.

The new guidelines also recommend that all countries should develop plans to phase out the use of d4T (stavudine, Zerit) in first-line treatment due to the high frequency of serious toxicities caused by the drug. These toxicities, such as peripheral neuropathy (nerve damage) and lipoatrophy (fat loss) are often irreversible. According to WHO d4T is still used by more than half of treatment programmes in low and middle-income countries.

The new recommendations are accompanied by new guidance on treatment for women to prevent mother-to-child transmission of HIV, and on infant feeding.

Women who do not need ART for their own health will now be eligible to receive antiretroviral drugs throughout pregnancy and for the entire duration of breastfeeding.

HIV-positive women will no longer be encouraged to wean their infants early. Instead, WHO is now recommending 12 months of breastfeeding for HIV-negative infants, in order to ensure that infants have a greater opportunity to benefit from breastfeeding. Although formula feeding is not ruled out, it will be left to individual countries to promote one policy for all women, depending on local circumstances.

Earlier treatment

WHO issued guidelines for treatment in resource-limited settings in 2003 and updated them in 2006.

The focus of the original guidelines was the scale-up of antiretroviral treatment by a public health approach – a standardised prescription for treatment that could be adopted by any health system, no matter how poorly resourced. The 2003 guidelines emphasised that eligibility for treatment could be determined by the presence of symptoms of advanced HIV disease – so-called WHO stage 4 disease.

Pressure for WHO to recommend earlier treatment has been growing for several years. A change in the guidelines began to look inevitable earlier this year when the CIPRA HT 001 study in Haiti was halted. This US-sponsored study was designed to evaluate whether earlier treatment, starting at a CD4 threshold of 350, had a significant effect on reducing death and illness in a low-income setting. The study was halted early after an interim analysis showed a significantly lower rate of deaths in the earlier treatment arm.

In June Dr Kevin M de Cock, outgoing head of the WHO’s HIV department told the 2009 HIV Implementers’ meeting in Windhoek, Namibia: "The world cannot allow a permanently two-tiered system of global AIDS treatment with late initiation of outmoded drugs reserved for the South.”

Today’s recommendations, released in advance of publication of the full adult treatment guidelines in early 2010, emphasise the use of CD4 counts in order to determine eligibility for treatment, in place of the previous model.

Treatment should now be initiated when a person’s CD4 count falls below 350, regardless of whether symptoms are present or not.

The shift to earlier treatment needs to be supported by a greater investment in laboratory monitoring, and the new guidance recommends that where available, viral load should be monitored every six months and treatment should be swtiched if viral load has risen above 5000 copies/ml. However, WHO states that access to treatment should not be denied if laboratory monitoring is not available.

Although the recommendation of earlier treatment has the potential to greatly increase the numbers in need of treatment, uptake of earlier treatment will be dependent on increasing the uptake of voluntary counselling and testing. At present the average CD4 count at which people in low and middle-income countries begin antiretroviral treatment is less than 200. The ART LINC international cohort collaboration reported that the average CD4 count at the time of treatment initiation in 2006 was 122 cells/mm3 in sub-Saharan Africa, 134 cells/mm3 in Asia, and 197 cells mm3 in Latin America.

The influential South African clinician Dr Francois Venter told the International AIDS Society conference in July that, for South Africa, the priority was to get people onto treatment, not earlier treatment, and that despite a big increase in HIV testing in South Africa in recent years, too many patients were being lost from care after diagnosis, only returning when seriously ill.

Country capacity to offer earlier treatment is also questionable, with reports of caps on treatment enrolment in several countries due to a shortage of funds. However WHO says that the incremental costs of an additional one to two years on ART – the estimated additional time on treatment – may be partly offset by decreased hospital and death costs, increased productivity due to fewer days sick, fewer children orphaned by AIDS and a drop in new HIV infections as a consequence of suppressed viral load.

An economic analysis of the South African situation, published earlier this year, estimated that earlier treatment in line with the new WHO recommendations would cost South Africa $1.5 billion over five years if the country’s health system was successful in diagnosing and treating everyone eligible for treatment, and $1.1 billion if half of those eligible received treatment.

Phasing out d4T

WHO is now recommending that national treatment programmes should phase out the use of d4T in first-line treatment due to the high frequency of serious toxicity. The drug has been the mainstay of antiretroviral treatment scale-up in resource-limited settings due to its low cost and its availability in cheap, generic fixed-dose combinations.

Instead, treatment programmes should use tenofovir or zidovudine (AZT, Retrovir). However, both these drugs are more expensive than d4T, and in the case of tenofovir, only available in three-drug fixed-dose combination with efavirenz (Sustiva or ), also more expensive than the other mainstay of treatment scale-up, nevirapine (Viramune). WHO acknowledged in its statement today that implementation of the recommendations will depend on national circumstances, resources and priorities.

Further information

The difficulties facing national treatment programmes in phasing out d4T and shifting to earlier treatment were reviewed in a June 2008 edition of HIV & AIDS Treatment in Practice, NAM’s electronic newsletter on HIV treatment in resource-limited settings, and in a June 2007 news report from the HIV Implementers’ meeting in Rwanda.

References

World Health Organization Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. November 30, 2009. Download at http://www.who.int/hiv/pub/arv/advice/en/index.html.

ART LINC Cohort Collaboration. Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America. Trop Med Int Health 13(7):870-9, 2008.