Treatment switches after CD4 count decline reduce risk of death by 75% in Zambia, Malawi

Carole Leach-Lemens
Published: 09 December 2011

Mortality was reduced by about 75% among adults experiencing immunological failure according to the World Health Organization (WHO) criteria who switched to a second-line regimen compared to those who remained on a failing regimen in two public sector ART programmes without access to routine viral load monitoring in Zambia and Malawi, researchers report in the advance online edition of AIDS.

Additionally in this collaborative analysis Thomas Gsponer and colleagues on behalf of the Southern African region of the International epidemiological databases to evaluate AIDS (IeDEA-SA) showed the less time spent on a failing regimen the lower the risk of death, HR:0.70 (95%  credible intervals (CI): 0.44-1.09), p=0.11 for each six months of shorter exposure.

An estimated 6.6 million people are now getting ART in resource-poor settings. As access to treatment increases so does the number of people experiencing treatment failure with a corresponding increase in the use of second-line treatment regimens.

Cost and the absence of the necessary laboratory infrastructure preclude the regular use of viral load monitoring in resource-poor settings, especially in rural areas.

Without viral load monitoring immunological (CD4 cell counts) and clinical criteria are used to determine treatment failure. However, the accuracy of such criteria to detect virological failure is poor. This may lead to unnecessary switching with many health care providers reluctant to switch using these criteria. So people are switched later and at lower CD4 cell counts compared to programmes where viral load monitoring is available, note the authors.

The authors chose to examine further the effect of switching to second-line ART on mortality in settings without viral load monitoring.

All adult patients experiencing treatment failure according to WHO immunological criteria from two public sector ART programmes in Lusaka, Zambia and Lilongwe, Malawi were included in the analysis. Clinical and immunological monitoring was done every three to six months. In both sites viral load testing is limited because of cost and operational difficulties.

Criteria for inclusion: all patients 16 years of age and over with immunological failure after January 1, 2004 based on any of the three WHO criteria: 1) CD4 cell counts staying persistently under 100 cells/mm3 2) a fall of CD4 cell counts below the baseline count and 3) a fall greater than 50% from the peak value.

Marginal structural models and inverse probability weighting of switching to compare mortality between patients who switched and those who did not and between those who switched immediately and those who switched later were used. The authors believe this to be the first study of its kind using this model in a resource-poor setting.

From 2004 to 2009 of the 80,937 patients who started ART, 2411 met the eligibility criteria and experienced failure; 96.1% (2317) from Zambia and 3.9% (94) from Zambia.

Of these 324 (13.4%) were switched to second-line ART during a median of 1.7 years of follow-up.

Median CD4 cell count in those who switched was lower at the start of ART and failure compared to those who did not: 80 cells/mm3 compared to 155 cells/mm3, p<0.001 and 77 cells/mm3 compared to 146 cells/mm3, p<0.001, respectively.

In addition to lower mortality, loss to-follow-up was also lower among people who switched compared to those who did not: 14.2 (6.8-25.9) compared to 50.5 (43.2-58.5) per 1000 person years, p<0.001, respectively.

After adjusting for baseline and time-dependent confounders the risk of death among those who switched to a second-line regimen immediately after failure was significantly lower than those who remained on a failing regimen (HR 0.25, 95% CI: 0.09-0.72, p=0.01).

27.2% (655) patients had at least one viral load measured between six months after starting ART and immunological failure. Viral load measurement was more common among those who switched compared to those who did not, but was not statistically significant.

The authors note that ideally a randomised clinical trial should be used to determine the causal effect of switching to second-line treatment among immunologically failing patients. But they caution this is highly improbable since it raises ethical concerns.

So observational data as provided in this study offer the best available evidence to guide and inform clinical practice and public health decisions on when and if to switch, they add.

The authors note that prognostic factors can distort results from observational studies. Inverse probability of treatment weighting was used to adjust for confounding by time-updated CD4 cell counts.

The authors note that while the reduction in death was significant it may have unknowingly included patients who met the immunological failure criteria but had an undetectable viral load.

While two public sector programmes were involved, the authors question how generalisable their findings are. These programmes are equipped with electronic medical records systems, have access to regular CD4 cell counts and are involved in an international collaboration of HIV cohorts. Yet, they nonetheless follow national guidelines for the public health approach common to many programmes in the region.

The authors conclude, “in ART programmes [in sub-Saharan Africa] switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after failure is diagnosed.”  

Adding that targeted viral load may further reduce unnecessary switching and recommend that future studies “investigate at what CD4 cell count levels patients should ideally be switched and should examine long-term outcomes including after second-line failure.”



Gsponer T et al. The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring. AIDS, advance online edition, doi: 10.1097/QAD.0b013e32834e1b5f, 2011.

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