The use of HAART for PMTCT is one of the most successful public health interventions of the HIV era in the United States.10
Despite rates of transmission remaining below 1% for the last 5 years of WITS,19
we found that 32% of the women who received HAART between 1998 and 2005 had a detectable HIV-1 RNA at delivery. This discrepancy may indicate successful peripartum prophylaxis efforts of mothers and infants, but it also highlights the fact that one of the cornerstones of PMTCT – maternal virologic suppression–was difficult to achieve in this cohort. MTCT continues to occur in the United States, and this transmission is at least in part due to factors associated with detectable maternal HIV-1 RNA at delivery. While rates of detectable viral load declined over time, a finding which is also consistent with CDC data,4
the high numbers of women on treatment with detectable HIV-1 RNA highlights the need for increased counseling of known HIV-infected women and aggressive treatment for the most vulnerable groups regardless of pregnancy status, both for PMTCT as well as overall maternal health.
In the current study, women who were most at risk were those who presented with a higher HIV-1 RNA and lower CD4+ count at enrollment. This was seen among women who were HAART–experienced and among women who were HAART-naïve prior to their pregnancy. For women who were HAART-naïve prior to pregnancy, this may have reflected more advanced disease and/or initiation of therapy later in pregnancy. For women who were HAART-experienced prior to pregnancy, this may have reflected either more advanced disease possibly refractory to antiretrovirals, or suboptimal use of antiretrovirals prior to pregnancy that was ultimately more resistant to subsequent regimens. Younger age and illicit drug use also significantly increased the odds of having detectable HIV-1 RNA at delivery in women who were HAART-naïve prior to pregnancy.
The type of HAART treatment did not significantly impact HIV-1 RNA levels at delivery, both before and after adjusting for enrollment factors, including HIV-1 RNA and CD4+ count. This finding was consistent for all women. The lack of superiority for boosted PI’s was a surprising finding in our evaluation of the impact of antiretroviral regimens on suppression of maternal HIV-1 RNA at term. While these findings are novel, it is important to interpret them with caution, given the relatively small numbers in each treatment group, and the observational design that may be prone to residual confounding. In addition, boosted PI’s may have been used more commonly in patients with more advanced disease, in whom antiretrovirals may have diminished effectiveness. We therefore believe that current treatment practices that recommend the use of ritonavir boosting when using PI’s in pregnancy should continue, pending further study of this question, ideally in randomized studies.
The loss of viral load suppression during pregnancy that occurred among 13% of women who initially had undetectable levels of HIV-1 RNA is of concern. It is unknown whether pregnancy itself increases the risk for loss of suppression. Factors specific to pregnancy may include increased medication intolerance (especially gastrointestinal), increased medication side effects (anemia’s or other), or altered pharmacokinetics. 20, 21, 22
Several studies have reported lower area under the plasma concentration time curve (AUC) in the third trimester with both lopinavir/ritonavir 23,24
and nelfinavir, 24
but the association between lower drug levels during pregnancy and virologic outcome at delivery has not been studied. Many experts, however, consider it to be reasonable to increase the dose of certain PI’s during the third trimester when viral load remains unsuppressed in the setting of good medication adherence. 25
Whether or not such dose increases might have reduced the loss of suppression in this cohort is unknown. We believe our findings warrant further study in trials where information on medication adherence, pharmacokinetics, and resistance can be obtained.
Women who were HAART-experienced prior to pregnancy differed from those who were HAART-naïve prior to pregnancy, both in enrollment characteristics as well as likelihood of virologic suppression at delivery. In general, women who were HAART-experienced were significantly more likely to be older, on public insurance, parous, have a more advanced CDC class, a longer duration of HIV diagnosis, and a lower CD4 count at enrollment. HAART-naïve women appeared to have generally less advanced disease at enrollment and were more likely to be virologically suppressed at term. This may in fact reflect disease stage, but could also reflect unmeasured sociodemographic factors, or lower rates of resistant virus among HAART-naïve women.
There were some significant trends within the cohort over time. There appeared to be fewer women who were HAART-naïve at enrollment in later years. This may reflect expanded screening for HIV and earlier treatment outside of pregnancy or more known HIV-infected women choosing to get pregnant. An important observation seen in our multivariable model was that the odds of having a detectable HIV-1 RNA at delivery declined with calendar year in the HAART-experienced group, even after adjustment for HIV-1 RNA and CD4+ cell count at enrollment. This may be reflective of increasing knowledge of the importance of viral load suppression at delivery and greater ability to achieve this in the HAART- experienced group as treatment options expanded, despite minimal changes over time with the HAART-naïve group. We did not find, however, that calendar year confounded associations with other factors included in the model.
This was an observational analysis, and prone to biases, including potential selection bias, and unmeasured confounding. We had limited information on medication dosage, patterns of resistance, adherence, and the exact timing of HAART initiation. In addition, we were only able to measure the initial regimen used in pregnancy, and viral suppression at delivery may have been affected by subsequent regimen changes. Because most women had started HAART before study entry, our first measured CD4+ cell count and HIV-1 RNA were not true “baseline” values, even for women who were HAART naïve prior to pregnancy. Despite these limitations, our study is one of the first U.S.-based observational analyses comparing the association between regimens and virologic suppression at delivery in the current era of HAART availability. Virologic suppression at delivery is an important risk factor for MTCT, and one that can be clinically measured. HIV-1 RNA suppression at delivery is a reasonable surrogate measure of success for antiretroviral therapy as an intervention to prevent MTCT.
In conclusion, our analysis suggests that women with lower CD4+ counts and higher HIV-1 RNA during pregnancy are at an increased risk for a detectable HIV-1 RNA at delivery. Persistently detectable HIV-1 RNA is particularly common among HAART-experienced women presenting with detectable HIV-1 RNA in pregnancy (57% of whom remained detectable at delivery). Of additional concern was the loss of virologic suppression by delivery among 13% of women with undetectable HIV-1 RNA at entry. Our findings suggest that efforts to improve suppression at term are warranted, particularly among women with lower CD4+ cell count and higher HIV-1 RNA.