TB, pregnancy, most common reasons for treatment changes in African study

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While changes in antiretroviral regimens are often impelled by side-effects, a considerable proportion of first-line changes in a west African cohort were found to be due to other issues, according to a forthcoming article in the journal AIDS.

Among 2012 HIV-positive Côte d’Ivoire adults taking antiretroviral therapy for the first time, modifications were most commonly made because of drug intolerance (12.4 cases per 100 patient-years), pregnancy (4.5 cases per 100 patient-years) and tuberculosis (2.5 cases per 100 patient-years).

The finding calls attention to the dilemma facing physicians who need to decide whether to prescribe nevirapine (Viramune) or efavirenz (Sustiva), which are both widely used in antiretroviral treatment programs in developing countries.

Glossary

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

first-line therapy

The regimen used when starting treatment for the first time.

active TB

Active disease caused by Mycobacterium tuberculosis, as evidenced by a confirmatory culture, or, in the absence of culture, suggestive clinical symptoms.

WHO stage

A simplified system to describe four clinical stages of HIV-related disease, based on clinical parameters (symptoms, weight loss and different opportunistic infections) rather than decreasing CD4 cell count. Stage I is asymptomatic, stage II mild symptoms, stage III advanced symptoms and stage IV severe symptoms (an AIDS diagnosis).

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

Because of drug interactions, nevirapine is not thought to be advisable for people who also need the anti-tuberculosis drug rifampicin.

At the same time, some research has suggested that efavirenz has the potential to cause birth defects.

The study looked at outcomes for 1472 women and 530 men who started taking antiretroviral therapy between June 2004 and November 2006. Eligibility for antiretroviral therapy was determined using 2003 World Health Organization (WHO) criteria, which called for treatment initiation at either clinical stage 4; CD4 cell count less than 200 cells/mm3; or clinical stage 3 and CD4 cell count 200-350 cells/mm3.

People with HIV-1 were given two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) – either nevirapine or efavirenz. Women on efavirenz were also prescribed hormonal birth control. People who had HIV-2 or both viral types were given two NRTIs and one protease inhibitor (PI).

The median CD4 cell count at the time of treatment initiation was 125 cells mm3. Nine percent of study participants had active tuberculosis disease, and another ten percent reported having active tuberculosis disease in the past.

Almost one-fourth of the cohort changed to another treatment regimen during a median of 19 months of follow-up. The rate of change was 20.7 per 100 person-years.

Rates and causes of treatment changes were reported for the three most common drug regimens: stavudine/lamivudine/nevirapine (d4T/3TC/NVP), taken by 32% of the full cohort; zidovudine/lamivudine/efavirenz (AZT/3TC/EFV), taken by 38%; and stavudine/lamivudine/efavirenz (d4T/3TC/EFV), taken by 25%.

Not surprisingly, the highest rates of first-line treatment changes occurred among people on the two stavudine-containing regimens: 34.0 per 100 person-years for d4T/3TC/NVP and 27.2 per 100 person-years for d4T/3TC/EFV. The AZT/3TC/EFV group had 10.5 changes per 100 person-years.

Stavudine is widely used in resource-limited settings for reasons relating to cost and convenience. However, stavudine frequently causes serious side-effects. WHO has recently called for this drug to be phased out of antiretroviral treatment programmes, and replaced with either tenofovir or AZT.

In 12.2% of all regimen changes, efavirenz was replaced with nevirapine for pregnancy-related reasons. Almost one-quarter of women who started antiretroviral therapy with an efavirenz-containing regimen switched to nevirapine for pregnancy-related reasons.

Six percent of all regimen changes occurred because study participants needed to begin taking rifampicin for tuberculosis. Eighteen percent of all people who first took nevirapine switched for that reason. When nevirapine needed to be discontinued to accommodate rifampicin use, it was replaced with efavirenz.

Among study participants who made first-line regimen changes because of drug intolerance, the highest rate of intolerance-related change was for stavudine (17.9 per 100 person-years), followed by nevirapine (6.3 per 100 person-years), zidovudine (3.9 per 100 person-years) and efavirenz (0.1 per 100 person-years).

Discontinuation of stavudine occurred increasingly throughout the study observation period, while discontinuation of the other three drugs mostly occurred during the first six months.

Statistical analysis that controlled for potentially confounding factors identified an association between intolerance-related d4T substitutions and older age, as well as an association between those substitutions and lower baseline CD4 count. Intolerance-related zidovudine substitutions were associated with baseline haemoglobin level and baseline tuberculosis status.

There are usually no serious medical concerns associated with the switch from nevirapine to efavirenz or vice versa, but the authors call attention to the programme management implications.

“In sub-Saharan Africa, drug forecasting and stable drug management systems are crucial to ensuring the success of HIV treatment programmes,” they note. “Reductions in rates of drug switches could contribute to the success of ART delivery programmes.”

While drug stock-outs were not one of the leading reasons for treatment changes in this study population, they did account for 5% of switches from ZDV/3TC/EFV and 6% of switches from d4T/3TC/EFV.

The authors also emphasise their findings about efavirenz. “Rates of … regimen modifications in patients taking [efavirenz] and any NRTI except for stavudine would be strikingly low if [efavirenz] was shown to be well tolerated for pregnant women,” they observe.

References

Messou E et al. Antiretroviral treatment changes in adults from Côte d’Ivoire: the roles of tuberculosis and pregnancy. AIDS (online edition) 2010.