Post-Peripartum Use of Viramune Safe After Six-Month Wait

BOSTON, Jan. 11 -- For women in developing countries who are HIV-positive, a dose of Viramune (nevirapine) during labor to prevent mother-to-child viral transmission does not preclude the safe renewed use of Viramune-based antiretroviral therapy after a six-month delay.

But use of Viramune-based antiretroviral therapy before the six-month delay increases the risk of resistance and virology failure, according to a study in Botswana by Shahin Lockman, M.D., of Brigham and Women's Hospital here, and colleagues.

Among 218 women in Botswana, those given a single Viramune dose during labor had similar virologic failure rates as those not previously exposed when both groups started Viramune-based antiretroviral therapy six months or more afterward (12.0% versus 7.8%, P=0.39), reported Dr. Lockman and colleagues in the Jan. 11 issue of the New England Journal of Medicine.

These results counter fears that this inexpensive staple for prevention of mother-to-child transmission in the developing world results in subsequent development of viral resistance.

In the United States, HIV-positive women typically are given Retrovir (zidovudine) for prevention of mother-to-child viral transmission, starting at 14 to 34 weeks of pregnancy with intravenous doses during delivery.

Delaying Viramune-based antiretroviral therapy may allow resistance mutations to fade to a low number of archived mutations in viral reservoirs, Dr. Lockman and colleagues said.

These results should be "reassuring for the many women who have received a single dose of nevirapine and to those who will receive it," they wrote.

The prospective study was part of a larger, mother-to-child transmission prevention trial in which women were randomized to receive Viramune or placebo during labor and all were treated with Retrovir from 34 weeks' gestation to delivery. Only those who later started Viramune therapy and had at least nine months of follow-up data were included in the analysis. Baseline characteristics were similar between groups.

Infants whose mothers received Viramune also received a single dose at 48 to 72 hours after birth. Only the 30 infants who were HIV-infected and later started on Viramune-based antiretroviral treatment were included in the analysis (15 in the placebo group).

Virologic failure was defined as a confirmed plasma HIV type 1 RNA level of at least 400 copies per milliliter during treatment, or less than a one log drop in the HIV-1 RNA level with a detectable plasma HIV type 1 RNA level.

By the six-month visit after starting antiretroviral treatment, virologic failure was significantly more common among Viramune-exposed women overall (18.4% versus 5.0% placebo, P=0.002), as has been found in other studies.

This difference appeared to be almost entirely accounted for by the group who started Viramune-based antiretroviral treatment within six months of the single dose. Among these 60 women, 41.7% of those in the Viramune group had virologic failure compared with none in the placebo group (P<0.001).

At one year after initiation of antiretroviral therapy, the findings were:

• Virologic failure was still more common among the overall group that received a single dose of Viramune (19.7% versus 9.6%, P=0.04),
• This effect was still concentrated among those who started within six months of delivery (45.8% versus 2.9% in the placebo group, P<0.001), and
• There was still no difference between groups among those that started at least six months after the single peripartum dose (12.0% versus 13.8%, P=0.76).

At two years after start of antiretroviral therapy, the researchers reported:

• Virologic failure remained more common among the Viramune group overall (27.9% versus 11.3%, P=0.008),
• The Viramune group that initiated therapy within six months still had higher virologic failure rates than those who were not initially exposed (45.8% versus 2.9%, P<0.001), and
• There continued to be no difference in the efficacy of Viramune between groups among those that delayed therapy at least six months after delivery (24.7% versus 17.1%, P=0.38).

There were similar results for the secondary endpoint of time to virologic failure.

The researchers found that virologic failure was significantly correlated with exposure to a single dose of Viramune or placebo and time to initiation of antiretroviral treatment (P=0.004). Time to initiation of therapy continued to be significantly associated with virologic failure even controlling for HIV-1 RNA levels and CD4+ cell count (P=0.004).

Among the 20 women in the Viramune group who had virologic failure by six months of treatment, 16 were tested for resistance mutations. The findings were:

• 18.8% had no detectable Viramune resistance mutations before or during treatment.
• 6.2% had resistance at baseline though not at virologic failure.
• 31.2% had no resistance at baseline but did at the time of failure.
• 43.8% had Viramune resistance both at points.

Among the infants, virologic failure was significantly more common in the single-dose Viramune group (P<0.001). At the six month visit after antiretroviral initiation, 10 infants in the Viramune group and one in the placebo group had virologic failure (76.9% versus 9.1%, P<0.001).

Although this difference in treatment response was large, the sample size was small and the patients also received perinatal Retrovir, the researchers cautioned.

"Although our findings raise concern about the efficacy of nevirapine-based antiretroviral treatment in infants receiving a single dose of nevirapine, pediatric data from other studies will be very important," they wrote.

Further follow-up among the women will also be necessary to evaluate the duration of virologic suppression since "mutations archived after exposure to a single dose of nevirapine may reemerge with a longer duration of nevirapine-based antiretroviral treatment," the researchers said.

Although most of the women in the trial (99.7%) had HIV type 1 subtype C, it is the subtype in which Viramune resistance is most likely to emerge. Women with other subtypes are likely to have at least as favorable of outcomes as seen in the study, the researchers noted.

The authors concluded that these data indicate that starting a Viramune based antiretroviral regimen is reasonable after six months or more following a single dose. However, physicians should consider starting non-Viramune-based regimens for women with advanced AIDS for whom it may not be safe to delay treatment six months or more after the single dose of Viramune at delivery, they said.