Recommendations of the U.S. Public Health Service Task Force on the Use of Zidovudine to Reduce Perinatal Transmission of Human Immuno deficiency Virus

10

MMWR

August 5, 1994

components of the ACTG Protocol 076 regimen should be recommended until
further information becomes available. This recommendation should be presented in the context of a risk-benefit discussion with the pregnant woman.
IV. Pregnant HIV-infected women who have a history of extensive (>6 months) ZDV
therapy and/or other antiretroviral therapy before pregnancy.
Discussion:
Women who have received extensive prior ZDV therapy may be infected with
viral strains with reduced susceptibility to ZDV. These resistant strains of HIV can
be transmitted from mother to fetus; however, the frequency with which such
transmission occurs is unknown.
Resistant virus appears to emerge more quickly if therapy is initiated at later
stages of HIV disease (21 ). The appearance of mutations associated with ZDV
resistance follows a temporal pattern, and the level of in vitro resistance is proportional to the number of mutations in the reverse transcriptase-coding region
of HIV (40). Phenotypically and genotypically diverse HIV populations can coexist in patients who are receiving ZDV therapy.
In one study, ZDV-resistant strains appeared earlier during ZDV therapy in
patients with advanced HIV disease than in patients whose ZDV therapy was
initiated at an early stage of the disease. After 12 months of ZDV therapy, viral
isolates from 89% of patients with late-stage disease and 31% of those with
early-stage disease were resistant (21 ). However, isolates from only 33% of latestage patients demonstrate high-level resistance (defined as a 100-fold decrease
in susceptibility [411). Resistant virus also was more likely to be isolated from
patients who had low CD4+ T-lymphocyte counts when therapy was initiated:
1-year estimated rates of resistance in patients with baseline CD4+ T-lymphocyte
counts of >400, 100-400, and <100 cells/gL were 27%, 41%, and 89%, respectively. In patients with advanced disease, high-level resistance develops after
6-18 months of therapy. However, in patients with early-stage disease, highlevel resistance appears to be delayed until after 24 months of therapy (22).
Therefore, ZDV-resistant strains are likely to be more common in women with
advanced disease who have received prolonged therapy.
ZDV-resistant viral strains also may be more common in persons receiving
alternative antiretroviral agents because their disease progressed while they
were receiving ZDV therapy. There is controversy regarding the association of
clinical disease progression during ZDV therapy with the development of ZDV
resistance and regarding whether resistance persists when therapy is changed
to an alternative antiretroviral agent (41 ). Some studies involving small numbers of children have indicated that in vitro susceptibility to ZDV is correlated
with clinical outcome, suggesting that ZDV-resistant isolates are associated with
diminished efficacy of ZDV and more rapid clinical progression (42,43). However, at least one study indicated that disease progression may be associated
more closely with the development of syncytia-inducing viral phenotype than
with resistance to ZDV (44). Change to alternative antiretroviral therapy has
been associated with reversal of ZDV resistance in some studies, but resistance
has been reported to persist for considerable periods of time after discontinuation of ZDV (23,45). The prevalence of ZDV-resistant viral strains in women