Debates about whether to start treatment at a CD4 count of 350 in developing countries ignore the fact that current programmes are doing very badly at retaining patients in care after diagnosis or starting people on treatment before they become seriously ill, Dr Francois Venter, President of the South African HIV Clinicians Society told the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention on Monday.
Speaking during a conference symposium on when to start treatment, Dr Venter pointed out that the current average CD4 count at which patients start treatment in South Africa is 87 cells/mm3.
Despite a huge increase in the number of people who undergo HIV testing – up to one-quarter of South African adults took a test in the past year, according to 2009 research by the Human Sciences Research Council – the average CD4 count at which patients in his Johannesburg clinic start treatment has not moved above 80 to 100 cells since 2004, Dr Venter said.
“We are still doing a terrible job of retaining patients in care, and we need to start looking harder at retention in care,” he said. “Are you delivered into a package of care that looks after you [after diagnosis]?” he asked.
A large number of patients were dying while waiting for the results of diagnostic tests and while undergoing treatment-preparation counselling, or during acute opportunistic infections.
“Around half of patients in my practice start antiretroviral treatment during or just after treatment of an acute OI,” said Dr Venter, but clinicians still lack definitive information about the most appropriate time to start antiretroviral treatment in conditions such as cryptococcosis, the second most common opportunistic infection in southern Africa, and there is limited awareness of data from the recently halted SAPIT trial, which shows that antiretroviral treatment should not be delayed in TB patients until the completion of the TB treatment course.
He also expressed concern about the implications of recent findings on the inflammatory effects of HIV infection for developing countries. “Cardiovascular disease is not usually seen as an African problem, but death-certificate analysis in South Africa recently revealed that diabetes and hypertension were among the most frequent causes of death.”
Similarly, South Africa is seeing overlapping epidemics of HIV and obesity. Potent cardiovascular risks may lead to a high rate of cardiovascular disease in people with HIV, Dr Venter argued. He also drew attention to the high rate of liver disease and hepatitis virus infection in the developing world, to data showing that uncontrolled HIV replication exacerbates liver damage, and to the high frequency of kidney disease in African-Americans with advanced HIV infection (people of African origin appear to have a high risk of HIV-associated kidney damage).
“The thing that filled me with fear [looking at the data on inflammation and HIV] was renal disease. Kidney transplants, dialysis, even prophylactic drugs to deal with proteinuria are difficult to obtain and expensive in this region.”
However, the priority group for earlier treatment is pregnant women, said Dr Venter. “Treating mothers is much easier than treating children”, although implementation challenges such as defining the best antiretroviral regimen for use in pregnant women remain.
Eighty-four per cent of maternal deaths and 47% of postnatal infant infections occur at CD4 counts below 350, he noted.
“We could meet the Millenium Development Goal 5 on reducing maternal mortality by raising the threshold to 350 for pregnant women.”
However, one of the major obstacles to early treatment in the developing world is the current reliance on d4T (stavudine) in first-line treatment.
Dr Venter said that when he conducted an informal survey of colleagues treating large number of patients on when they would choose to start treatment, significant reservations about earlier treatment using d4T were expressed.
At a satellite meeting organised by Médecins sans Frontières, Dr Venter warned that activist demands for the better-tolerated drug tenofovir (Viread) to replace d4T in South Africa’s first-line regimen needed to be considered in the light of poor progress towards delivering treatment to those in urgent need. “A lot of our patients are dying without even having access to d4T.” He also warned that South Africa’s national treatment programme “is pretty much committed to staying with d4T for the next three to four years”.
He called for prospective research to quantify the effects of lower doses of d4T in the region, and Dr Graeme Meintjes of GF Jooste Hospital in Cape Town told the satellite meeting that the incidence of lactic acidosis and hyperlactataemia had fallen dramatically since the adoption of a 30mg adult dose of d4T in 2006.
Starting treatment in the developed world
In the developed world national US, British and European guidelines now concur that treatment should be recommended to all patients with CD4 counts below 350.
While US cohort data suggest benefits to starting treatment before the CD4 count falls below 500, another major cohort analysis did not find an additional benefit to starting treatment at CD4 counts above 400, and an international randomised trial called START is currently recruiting patients to determine whether starting treatment at a CD4 count above 500 results in less death and illness than starting at the currently recommended threshold.
Dr Jose Gatell of Hospital Clinic, University of Barcelona, highlighted that current European AIDS Clinical Society treatment guidelines state that antiretroviral treatment should be considered for all diagnosed patients.
He warned “We cannot wait until completion of the START study to make decisions.”
Even in resource-rich settings cost of earlier treatment is not going to be minor issue, said Gatell.
He cited modelling by his own team which showed that while delaying treatment until a CD4 count of 350 is reached might save 30% over five years when compared with treating before the CD4 count falls below 500, when considered over a 30-year timeframe the saving in medical costs attributable to delayed treatment fell to 13%.
But to achieve an extended period of healthy life, normalisation of CD4 counts needs to be achieved. Professor Gatell pointed to research showing that normalisation of CD4 counts for at least five years above 500 cells is necessary in order to eliminate the difference in mortality between people with HIV and the general population.
Nevertheless, a substantial proportion of patients continue to fail to reach this CD4 level with current treatment due to late initiation of treatment, he noted. Therefore all patients with a CD4 count below 350 should be offered treatment unless there is a specific contraindication.
Gatell also highlighted the need to consider chronic inflammation caused by viral replication in untreated patients with higher CD4 cell counts, which may lead to an excess of non-AIDS-defining serious illness in this population when compared with the general population.