Professor Andrew Whitelaw, Infection Control Society of Southern Africa
A 27-year old woman was diagnosed with HIV in 2005 and started on ART. She has complex social circumstances and defaults recurrently. In February 2012 she presents to the clinic at 28 weeks pregnant, after defaulting ART for the seventh time in May 2011. Previous treatment regimens included the following:
3TC, NVP, D4T,
3TC, AZT, NVP
TDF, 3TC, EFV - defaulted May 2011
At this stage she has an absolute CD4 count of 75 cells/mm3 and a viral load of 52 905 copies/ml. She is initiated on TDF, 3TC, Aluvia (Lopinavir / ritonavir).
Shortly after starting ART again in Feb 2012 she is diagnosed with INH mono-resistant tuberculosis, on a line probe assay.
The baby is born at 36 weeks gestation with a birth weight of 2840g, and is clinically well at birth.
Question 1: HIV Issues
A) What is the best ARV strategy for an infant whose mother is failing second line treatment?
Answer to Q1.a
In South Africa we have approximately 300 000 HIV-related pregnancies per year. PMTCT options depend on the mother’s stage of disease and her CD4 count:
Our national PMTCT program does not account for mothers failing second line therapy and so management of these mothers and babies often is inadequate.
It would be ideal to perform genotype resistance testing on the mother prior to delivery so that the optimal combination of drugs can be chosen for the baby prior to delivery. Unfortunately resistance testing is not readily available and therefore the combination of drugs chosen for PMTCT is based on the mother’s antiretroviral history and extrapolated from adult resistance data.
In this case it would be prudent to use a three drug combination for PMTCT, rather than single dose NVP or AZT because if the baby is infected in utero or peripartum, the combination will serve as early treatment and decrease the risk of resistance that would arise from giving single drug treatment to a baby that is HIV positive. A possible regimen would be 3TC, Abacavir and Kaletra or 3TC, AZT and Kaletra. The mother has been on 3TC and Abacavir and so she would most probably be resistant to DDI.
The rationale for including AZT intrapartum when a woman is known to harbor virus with AZT resistance is based on several factors. Data thus far have suggested that only wild-type virus appears to be transmitted to infants by mothers who have mixed populations of wild-type virus and virus with low-level AZT resistance. Other studies have suggested that drug-resistance mutations may diminish viral fitness and possibly decrease transmissibility. AZT crosses the placenta readily and has one of the highest maternal-to-cord blood ratios among the nucleoside analogue agents. In addition, AZT is metabolized to the active triphosphate within the placenta, which may provide additional protection against transmission. Metabolism to the active triphosphate, which is required for activity of all nucleoside analogue agents, has not been observed within the placenta with other nucleoside analogues that have been evaluated (didanosine and zalcitabine). AZT penetrates the central nervous system (CNS) better than other nucleoside analogues except stavudine, which has similar CNS penetration; this may help to eliminate a potential reservoir for transmitted HIV in the infant. Thus, intrapartum administration of AZT currently is recommended even in the presence of known resistance because of the unique characteristics of the drug and its proven record in reducing perinatal transmission.
Question 1.b: When is the optimal time to do the PCR?
Answer to Q1.b
The routine time to do the PCR is at six weeks when the infant comes to the clinic for their first vaccinations. This timing is probably sub-optimal for all infants with imperfect PMTCT (antenatal ARVs commenced after week 20 of pregnancy, but the guidelines still need to adapt. For this infant, given the background of poor adherence, the PCR should be done on day one or two. If this early PCR is positive then the baby can continue the 3 drug regimen and be referred to the infectious disease clinic without delay. If the PCR is negative it would need to be repeated at six weeks as the early PCR’s can be falsely negative especially if the infant is receiving antiretrovirals.
Question 2.a: What is the best prophylaxis for an infant in who has a close contact with mono-INH resistant TB?
Answer to Q2.a
The first management step in an infant born to a mother with TB is to screen for TB disease either transmitted as a congenital infection or peripartum. Once active disease is excluded, a decision regarding choice of IPT can be made. In all cases BCG is delayed. If the mother has drug sensitive TB then the usual prophylaxis is 6 months of INH but 3 months of INH and Rifampicin can also be given. If the mother has INH resistant TB, the recommendation is to use INH and Rifampicin at normal doses (10mg/kg) for 6 months and if the mother has MDR TB then INH, Ethambutol and Ofloxacin/Levofloxacin is given for 6 months. After prophylaxis is complete, a mantoux should be done – if positive, no BCG is given and if it is negative, a BCG can be given in HIV negative children. It’s important to remember that Lopinavir requires ritonavir boosting from a 4.1 to 1.1 ratio when using Rifampicin.
Outcome of the case
INH and rifampicin were prescribed for prevention ART. The mother defaulted again and the infant was hospitalized with PCP at 4 months of age. The PCR was positive for HIV. ART was commenced (LPV/r + ZDV + 3TC). Abacavir resistance was assumed, therefore not used. LPV/r likely to be effective despite non-adherence in the mother
Reasons for poor adherence should be assessed with active intervention. Keeping the infant in a place of safety to ensure better adherence would have been preferable.
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