Palacios R, Senise JF, Vaz MJR, Diaz RS, Castelo A. Short-term antiretroviral therapy to prevent mother-to-child transmission is safe and results in a sustained increase in CD4 T-cell counts in HIV-1-infected mothers. HIV Med 2009;10:157-62.
Antiretroviral drugs can reduce mother-to-child transmission (MTCT) of HIV by lowing plasma viral load in pregnant women or through post-exposure prophylaxis in newborns.(1) Currently, WHO guidelines recommend that all pregnant women who do not yet need antiretroviral therapy (ART) for their own health should receive a short course of antiretroviral prophylaxis to prevent MTCT.(2) These regimens are discontinued after childbirth for women for whom continued ART is not indicated. Recent studies have highlighted the potential negative consequences of discontinuation of antiretroviral (ARV) drugs in HIV-1 infected persons. Negative outcomes are attributed to the decrease in CD4 count and increase in HIV-1 viral load that follow ARV interruption.(3)
To assess the effect of withdrawal of short-term antiretroviral therapy (START) after birth on CD4 cell counts and viral load dynamics
Hospital São Paulo, in São Paulo, Brazil
Prospective cohort study
Asymptomatic HIV-1 infected pregnant women, presenting with CD4 counts of >300 cells/µL, who received perinatal medical care between 2000 and 2005 at Hospital São Paulo
Time to detection of CD4 cell count of <300cells/µL following discontinuation of START; time to reinitiate ART after prophylaxis; difference between paired tests before and after START in terms of CD4/CD8 cell counts and HIV-1 viral load
All participating women received START containing two nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. If the patient had no other indications for treatment, ART was discontinued within four weeks after delivery. Women were excluded from analysis if CD4 cell counts were not available before initiating prophylaxis or if it was necessary to resume ART within eight weeks after delivery.
Patients were typically evaluated within eight weeks after delivery and again once every three to four months. Evaluations included a complete physical examination and laboratory tests consisting of HIV-1 viral load determination and CD4 cell count.
A total of 72 HIV-1-infected pregnant women who received START as part of their prenatal care during the study period were included in the analysis. Three women became pregnant twice during the study period, so in total 75 prophylactic regimens were prescribed. Median duration of START was 10 weeks (IQR 8.4-11.7), and median gestational age at start of treatment was 27.9 weeks (IQR 26.6-30.0) The START regimen included nevirapine (NVP) in 47 cases, nelfinavir (NFV) in 19 cases and lopinavir/ritonavir (LPV/r) in nine cases. NVP was replaced with NFV in five cases due to rash toxicity, and NFV was replaced with LPV/r in two cases due to gastrointestinal toxicity. In all but five pregnancies, HIV-1 viral load was undetectable at delivery. After discontinuation of START, an average of 6.4 samples per subject was collected for evaluation.
Comparing results of laboratory tests between the first evaluation after discontinuation of prophylaxis (START prophylaxis withdrawal) and pre-START values, CD4 cell counts and CD4/CD8 ratios were found to be significantly higher at prophylaxis withdrawal (P<0.001 and P=0.045, respectively). There was no significant difference between the two time points in viral load (P=0.308). Comparing later laboratory results with those from START prophylaxis withdrawal, no significant difference in CD4 cell count was found (P=0.308), but there was a significant decrease in the CD4/CD8 ratio (P<0.001).
The CD4 count decreased to <300 cells/µL in 14 (19%) of 75 cases evaluated. Twelve cases were censored due to new exposure to ART. Estimated mean time to detection of CD4 cell count <300 cells/µL was 180.6 weeks (95% confidence interval [CI]: 157.3-203.9); median time was 198.1 weeks (95%CI: 147.4-248.9). Cumulative follow-up time was 120.6 person-years. Results from Cox proportional hazards models suggested that four variables were significantly associated with CD4 cell count falling below threshold: exposure to ART prior to prophylaxis (RH 11.82; P=0.005), detectable HIV-1 viral load (≥400 copies/mL) at START withdrawal (RH 33.84; P=0.001), higher pre-START CD4 T-cell count (RH per 100 cells/µL 0.53; P=0.006) and CD4 T-cell count increase during prophylaxis (RH per 0.1 increase from pre-START value 0.81; P=0.024).
Estimated mean time to reinitiate ART after prophylaxis was 186.2 weeks (95%CI: 164.0-208.5). Cumulative follow-up time for this analysis was 126.6 person-years.
The authors conclude that data from this small study suggest that withdrawal of antiretroviral prophylaxis (START) appears to be safe for women with a pre-START CD4 T-cell count of >300 cells/µL. They note that the data presented highlight the importance of virological success as a prerequisite for prophylaxis withdrawal. Factors that seem to be related to increased duration of time until falling below CD4 threshold and re-initiation of treatment in women post-START discontinuation were presenting a high baseline CD4 T-cell count, not having been previously exposed to ART, and suppressing viral replication to undetectable levels and increasing CD4 counts after prophylaxis.
Using the Newcastle-Ottawa quality assessment scale for cohort studies, this study received 8 out of 9 points. One point was deducted because there was no unexposed cohort. Study authors acknowledged that results from the study are limited due to the absence of a control group of pregnant women without prophylaxis, but noted that inclusion of the control was not feasible due to ethical and logistical constraints.
Findings from this study are consistent with previous findings regarding ART discontinuation. However, the effect of short-course ART on HIV-1-infected women at different stages of disease progression is still unclear. The risk of future treatment failure as a result of drug resistance after prophylaxis withdrawal should be weighed against the potential consequences of maintaining the patients on medication. In HIV-1-infected individuals for whom ART is not yet indicated, a short-course of ARV drugs may have the benefit of increasing CD4 cell count, and raising the "CD4 count set-point." Additional studies are needed to determine if a higher CD4 cell count set-point induced by a short period of ART use might delay the need for further ART.
- Volmink J, Siegfried NL, van der Merwe L, Brocklehurst P. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev 2007;1.
- WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. 2006 version. Abstract not available.
- El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4 count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-96.