CROI: Further evidence that short-course PMTCT prophylaxis compromises mother's future treatment

Single-dose nevirapine (Viramune) is not the only component of short-course prophylactic regimens for prevention of mother-to-child transmission that may be compromising a mother's future treatment options, the French AIDS research agency reported this week at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles. Short perinatal courses of AZT/3TC that result in 3TC resistance are also causing mothers to experience an inferior virologic response when they eventually start triple drug antiretroviral therapy for their own health, and should be avoided in favour of triple-drug antiretroviral therapy (ART) during pregnancy, the investigators recommend.

Several previous studies have now shown that nevirapine resistance acquired as a result of taking a single dose of nevirapine at the time of childbirth may compromise a woman's subsequent virological response to treatment, although a recently published study carried out in Zimbabwe suggested that the risk of a poor response declined if treatment was delayed for at least six months after delivery.

However, studies examining the contribution of other agents to the prevention of mother-to-child transmission have led to women acquiring resistance to other drugs, notably 3TC.

Investigators from the Ivory Coast and France studied the response to triple-drug antiretroviral therapy in a prospective cohort of women who had previously taken single-dose nevirapine (sd-NVP) or short-course zidovudine (AZT, Retrovir) with or without lamivudine (3TC, Epivir) to prevent of mother-to-child transmission (PMTC).

A total of 247 ART-treated women who had initiated either an efavirenz- or nevirapine-based regimen taken alongside either stavudine (d4T, Zerit) or AZT, plus 3TC, were included in the analysis.

Of the 138 (56%) who had previously been pregnant and had received prior PMTC treatment, 86 had received a combination of short-course AZT/3TC with single-dose nevirapine; five had received short course AZT/3TC only; 52 had received short course AZT with single-dose nevirapine; and two had received single-dose nevirapine only.

Outcomes were compared with a control group of 109 women who had not been exposed to any antiretroviral drugs prior to commencing ART.

Data from genotypic resistance tests undertaken four weeks post partum were provided for most – but not all – of the women. However, no AZT-related mutations were detected in the 115 of the 136 previously AZT-exposed women who underwent resistance testing.

In contrast, 3TC-associated resistance mutations were seen in 11 (15%) of the 73 tested women who had previously been exposed to 3TC.

Prevalence of nevirapine-associated mutations was found to be much higher in women previously exposed to single-dose nevirapine in combination with short-course AZT without 3TC. Whereas just three (4.1%) of the 73 women tested who had received short-course AZT/3TC with single-dose nevirapine were found to have nevirapine-associated resistance mutations, sixteen (38.1%) of the 42 tested women who received single-dose nevirapine with short-course AZT without 3TC had nevirapine-associated resistance mutations four weeks post partum.

NNRTI-based ART was initiated at a median CD4 cell count of 188 cells/mm³ a median of 19 months following exposure to PMTCT treatment.

A total of 42 (19.2%) out of 219 women experienced virological failure – defined by a plasma viral load above 500 copies/ml – after twelve months on ART.

However, when response was analysed according to resistance detected four weeks after delivery, it was discovered that 50% of women with 3TC resistance experienced treatment failure, compared with 18.9% of 3TC-exposed women without 3TC resistance.

Among nevirapine-exposed women the failure rates were 27.8% in women with resistance and 18.6% in women without resistance.

In both cases there was no significant difference in response between drug-exposed women lacking resistance and the unexposed control group.

Multivariate analysis that controlled for nevirapine exposure/resistance, maternal age, WHO clinical stage, and excessive haemoglobin found that 3TC-resistance mutations post partum was associated with virological failure (adjusted odds ratio [aOR] 6.86, 95% CI 1.1 to 42.9).

Exposure to single-dose nevirapine regardless of whether this resulted in the detection of post-partum nevirapine-associated mutation was found to be not statistically associated with virological failure (aOR 1.8, CI 0.5 to 6.5 for NVP resistance; aOR 0.4, CI 0.1 to 1.4 for NVP exposure without resistance).

Other factors associated with virological failure included poor self-reported adherence (aOR 12.7, 95% CI 3.0 to 53.9) and baseline CD4 count below 200mm³ (aOR 0.3, CI 0.2 to 0.8).

Immunological failure – defined by an absolute drop in the CD4 cell count by 30% from the woman’s peak CD4 cell count – was seen in 26 (11.1%) out of 235 women. Poor adherence (aOR 12.3; CI 3.2 to 47.8) was found to be the only significant factor associated with immunological failure.

Exposure to 3TC and/or nevirapine, regardless of the detection of post-partum resistance mutations, was found to be not associated with immunological failure (p = 0.57 and 0.12, respectively) in multivariate analysis that controlled for baseline CD4 count, WHO clinical stage, age and excessive haemoglobin.

Francois Dabis of the University of Bordeaux, presenting the results, said the findings reinforced the WHO recommendation for three-drug antiretroviral therapy during pregnancy rather than the use of single-dose nevirapine plus AZT/3TC.