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HIV and AIDS
Advantages and Disadvantages of New Antiretroviral Agents in
Women with HIV and Hepatitis C Virus Co-infection
a report by
Phyllis C Tien
Assistant Professor of Medicine, University of California, San Francisco, and Staff Physician, Veterans Affairs Medical Center, San Francisco
An understanding of the efficacy and safety of new antiretroviral drugs in in the incidence of rash were not reported, likely because of the small
HIV-infected women is imperative. Women are increasingly bearing the number of women included in the trial (n=19 in the treatment arm; n=25 in
brunt of the HIV/AIDS epidemic worldwide. In the US, the proportion of the placebo arm). The pharmaceutical package insert states that in clinical
AIDS cases in women has increased from 7% in 1985 to 27% in 2006; trials rash was generally considered mild or moderate, mainly occurred in the
African-American women are disproportionately affected.
1
Furthermore, second week of therapy and was infrequent after four weeks; about 2% of
women are often co-infected with the hepatitis C virus (HCV),
2
which poses patients receiving etravirine discontinued therapy due to rash. A small
additional challenges in the selection of antiretroviral drugs. Antiretroviral percentage (<0.1%) of patients developed severe and potentially life-
drugs are primarily metabolised in the liver, and underlying liver damage threatening skin reactions, including Stevens-Johnson syndrome and
from HCV infection may lead to elevated drug levels. The use of some erythema multiforme. Patients who had previously developed NNRTI-
antiretroviral drugs may also worsen liver damage due to direct toxicities of associated rash did not appear at increased risk.
the drug. However, data are limited regarding the efficacy and safety of
recently approved antiretroviral drugs in HIV-infected women with and Neuropsychiatric events, which have been commonly reported with
without HCV infection, due to the paucity of women and those with HCV efavirenz, were also common in DUET-1 and DUET-2, but there was little
co-infection in clinical trials. Early studies have suggested that women may difference in the incidence of neuropsychiatric events between the etravirine
be at increased risk of adverse events to antiretroviral drugs than men with arm and the placebo arm. In these trials, neuropsychiatric events included
HIV infection.
3–5
This article reports on the available data in HIV-infected reports of headache, somnolence, dizziness, memory impairment, insomnia,
women regarding the adverse effects of recently approved antiretroviral anxiety, depression or nightmare. Sex differences in the incidence of
agents, including new highly potent drugs from the protease inhibitor (PI) neuropsychiatric disorders were not reported in either DUET-1 or DUET-2.
and the non-nucleoside reverse transcriptase inhibitor (NNRTI) classes and
new classes of drugs such as the chemokine (C-C motif) receptor 5 (CCR-5) With regard to hepatotoxic events, in both DUET-1 and DUET-2 grade 3 or
inhibitors and integrase inhibitors. We also review the reported adverse 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
effects of older NNRTIs and PIs in the context of newer antiretroviral agents. elevations (defined as aminotransferase levels >5 times the upper limit of
normal) occurred in 3 and 2%, respectively, of patients in the etravirine arm.
Etravirine In the placebo arm, grade 3 or 4 events in AST and ALT both occurred in
Etravirine is the first NNRTI to be approved for use in HIV-infected persons in 1%. The proportion of patients with hepatitis B virus (HBV) and/or HCV was
nearly 10 years. Etravirine, which is prescribed as two 100mg tablets twice comparable in each arm, ranging from 11 to 13%. No specific warnings or
daily, is unique in that it has demonstrated antiviral activity in patients with precautions against the use of etravirine in those with HBV and/or HCV
existing NNRTI resistant virus. DUET-1
6
and DUET-2,
7
two randomised, infection are listed in the pharmaceutical package insert for etravirine.
double-blind, placebo-controlled trials of treatment-experienced adult
patients with virological failure on stable antiretroviral therapy and Rash and liver enzyme abnormalities are the hallmark adverse effects of
documented genotypic evidence of NNRTI resistance, viral load >5,000 nevirapine, and neuropsychiatric disorders are the hallmark adverse effects
copies/ml and three or more primary PI mutations, found that a higher of efavirenz. Women are thought to be at increased risk of nevirapine-
proportion of patients in the etravirine arm than in the placebo arm achieved induced rash
8,9
due to gender-based pharmacokinetic differences leading
an undetectable viral load after 24 weeks (56 versus 39% in DUET-1; to increased concentrations of nevirapine in women compared with men
62 versus 44% in DUET-2). It should be noted that all patients also received when given the same dose of the drug.
10
Single-nucleotide polymorphisms
darunavir with low-dose ritonavir and investigator-selected nucleoside in genes that encode the hepatic enzyme CYP2B6, which is primarily
reverse transcriptase inhibitors (NRTIs). responsible for nevirapine and efavirenz metabolism, have been associated
Similar to the NNRTI nevirapine, rash was a commonly reported side effect
Phyllis C Tien is an Assistant Professor of Medicine at the
of etravirine and appeared to be more common in women than in men. In University of California, San Francisco and a Staff Physician
DUET-1,
6
the incidence of rash over 24 weeks of therapy was 20% in the
at the Veterans Affairs Medical Center in San Francisco. She
is the Principal Co-Investigator of the Northern California
etravirine arm compared with 10% in the placebo arm (p<0.01); in DUET-2,
site of the Women’s Interagency HIV Study (WIHS) and the
there was a trend towards a higher incidence of rash in the etravirine arm
Study of Fat Redistribution and Metabolic Change in HIV
(14 versus 9%; p=0.0723). Among those on etravirine in the DUET-1 trial,
infection (FRAM). Her research has focused on adipose
tissue and metabolic disorders in HIV-infected women and
34% of 41 women reported rash compared with 18% of 263 men the impact of hepatitis C virus infection on these disorders.
(p=0.0192). Sex differences in the severity of rash or frequency of treatment
E:
ptien@medicine.ucsf.edu
discontinuation due to rash were not observed. In DUET-2,
7
sex differences
© TOUCH BRIEFINGS 2008 39
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