[Ip-health] Is NVP safe for MTCT? Help needed

[Gonsalves, Gregg]

From our newsletter, Treatment Issues
Vol. 15, No. 1
GMHC's Treatment Issues
January 2001
Sex Differences in Nevirapine Rash and Hepatitis top
By Bob Huff
Last year, the AIDS world was rocked when news came that the South African
Medicines Control Commission had halted a study of an experimental HIV drug
after two women in the trial died and several others developed severe liver
disease. Coming in the months leading up to the International AIDS
Conference in Durban, this episode catapulted the problems of bringing HIV
treatments to South Africa into the international spotlight.
The experimental drug in the trial was FTC, a compound in the same
therapeutic class as AZT and ddI. But blame for the women's deaths came to
rest on one of the other drugs the women received in their combination
cocktail: Nevirapine, an approved, non-nucleoside reverse transcriptase
inhibitor already at the center of another raging controversy about access
to treatment in South Africa. 
A Breakthrough for Treatment in Africa?
A widely hailed study (HIVNET 012) reported in 1999 that, for only four US
dollars, a single dose of nevirapine (Viramune) given to a pregnant woman
about to give birth and another dose to her baby could dramatically reduce
the chances that the infant would be infected during labor and delivery. For
the first time it seemed a grip had been gained on the intractable problem
of treating HIV in poor countries. Nevirapine for prevention of
mother-to-child HIV transmission was effective, it was practical and it was
relatively affordable. But was it safe? South African government officials,
reluctant to spend scarce resources on saving the babies of HIV-infected
mothers, claimed there was too little known about the side effects of
nevirapine to make it widely available. Ominously, the FTC trial deaths
seemed to back them up.
A close look at the experience with single-dose nevirapine finds little
cause for concern. In the HIVNET 012 study, 310 pregnant women received
single-dose nevirapine and another 308 women received AZT just before giving
birth. The rates of adverse events and drug-related toxicity were observed
to be similar in the groups. The incidence of laboratory abnormalities was
also similar in each group. Mild to moderate rash was reported for four
mothers in the nevirapine group and five in the AZT group. Among the babies,
nine in each group had a mild or moderate rash. No serious rashes were
reported for any participants.1 In another large trial of nevirapine
involving 652 pregnant mothers in South Africa who each received two doses
of the drug, there were no episodes of liver toxicity or serious rash
reported.2
Because no placebos were used in these trials, one cannot conclude that the
risks of adverse events are any greater or lesser for mothers who do not
receive antiretroviral drugs just before birth. And the long-term effect
upon the development of treated children can only be determined by years of
follow-up. But the low rates of serious adverse events observed suggest that
these treatment regimens are safe, at least in the short term. So safe, in
fact, that the HIVNET authors proposed that presumptive treatment of all
pregnant women with single-dose nevirapine may be justified in settings
where HIV testing and pre-test counseling are not affordable. 
But what caused the deaths and liver disease in the FTC trial and was
nevirapine responsible? In a complicated stratified trial design,
participants received FTC or lamivudine (3TC, Epivir) plus, depending on
their baseline viral load, either nevirapine or efavirenz (Sustiva/Stocrin,
another drug in the same class as nevirapine). Participants also received
stavudine (d4T, Zerit) as a background nucleoside analog to round out the
cocktail. All participants were monitored for elevated liver enzyme levels,
the standard laboratory markers for the development of hepatitis. There were
no reported differences in the incidence of severe (Grade 4) liver enzyme
elevations between those who received 3TC and those who received FTC. Nor
were any differences observed in these enzyme levels between blacks and
non-blacks in the study. But of 385 patients receiving nevirapine in the
trial, 36 (9%) had Grade 4 liver enzyme elevations while no such liver
enzyme abnormalities were observed in 83 patients receiving efavirenz. This
clearly pointed the finger at nevirapine. And, as we later learned from a
report at the Fifth International Congress on Drug Therapy in HIV Infection
in Glasgow, Scotland last November, women in the trial were twice as likely
as men to experience a Grade 4 elevation of liver enzymes during the first
four weeks of taking nevirapine. This is compelling evidence from a
randomized trial that there may be a sex difference in the likelihood of
liver disease for those who receive nevirapine.3
PEP Tragedies
About the same time as the nevirapine crisis was developing in South Africa,
in the United States an HIV-negative African-American healthcare worker
suffered a needle-stick accident as she was drawing blood from an
HIV-infected patient. She was placed on a post-exposure prophylaxis (PEP)
protocol containing AZT, 3TC and nevirapine. Fourteen days after starting
the drugs, she developed malaise, fatigue, fever and chills. At 20 days, the
HIV drugs were halted after her liver enzyme levels increased dramatically
above the normal range. A week later she developed liver failure and went
into a coma. She subsequently received a liver transplant, recovered and
remained HIV-negative six months after the accident.4
Two more tragic case reports involving post- exposure prophylaxis were
presented at the Glasgow conference. Two women who had been raped were
treated with a PEP regimen containing nevirapine. Both women required liver
transplants after liver disease developed within a month on the regimen.5
And in yet another needle-stick accident, a female health-care worker in
Chicago complained of nausea and anorexia eight days after starting a PEP
regimen containing nevirapine. She subsequently developed a severe rash
despite discontinuing the drug after the first symptoms occurred.6 Due to
these and other cases, the U.S. Centers for Disease Control (CDC) in January
2001 warned against the routine use of nevirapine in post-exposure
prophylaxis regimens.7
Background to the Warnings
January 2001 marked the tenth anniversary of the first use of nevirapine in
humans. The problems with skin rash and liver enzyme abnormalities were
detected during the earliest trials of the drug. These eventually led to
manufacturer recommendations that patients start nevirapine treatment at a
lower dose for two weeks until it was clear the full dose could be safely
tolerated. After several years of clinical experience with nevirapine and a
mounting number of serious adverse reactions, culminating in the South
African deaths, the European Medicines Evaluation Agency (EMEA) issued a
strong public statement in April of 2000 drawing sharp attention to the risk
of liver disease. The statement stressed the importance of following the
two-week lead-in period, intensive monitoring during the first eight weeks
of therapy and immediate discontinuation of nevirapine if certain symptoms
occur. Of particular concern are symptoms of severe rash, hypersensitivity
reaction or hepatitis, including elevated liver enzymes.8
These warnings were strengthened six months later when the manufacturer sent
a letter to U.S. health care professionals extending the critical initial
period of close monitoring to 12 weeks. Yet, as noted in that warning,
approximately one-third of adverse events have been reported to occur after
12 weeks.9
Despite the strength of these warnings to the medical community, despite the
doubled rate of hepatitis among women in the FTC trial, and despite an
apparent preponderance of case reports about severe and fatal adverse events
involving women, there have been no official cautions about any particular
danger for women starting nevirapine. 
Sex Differences in Nevirapine Rash
Recently, additional evidence was published that says women may have more
frequent skin-related adverse events when starting nevirapine. An article in
Clinical Infectious Diseases (January 2001) reports on a retrospective
cohort study that finds likely significant differences in the incidence of
nevirapine-associated rash between men and women.10
The researchers examined the medical records of all patients from three
large U.S. HIV clinics who received nevirapine for at least 30 days during
the period from 1993 through September 1998. Patients who discontinued
nevirapine due to severe skin rash prior to 30 days on treatment were also
included. The patients studied had been treated in clinics at Washington
University in St. Louis, the University of North Carolina in Chapel Hill and
at UCSF in San Francisco. The primary outcome of interest was a report of
severe (Grade 3 or 4) rash during the first 90 days of nevirapine treatment.
A secondary outcome was discontinuation of nevirapine due to any degree of
rash.
The search of medical records found 358 individuals (95 women; 263 men) from
the three sites that met the entry criteria for nevirapine use. The overall
incidence of severe rash during the first 90 days after starting nevirapine
was 3.4 percent. But women were eight times more likely to have had severe
rash than men, with an incidence of 9.5 percent compared to 1.1 percent for
the men. Also, women were five times more likely to have discontinued
nevirapine due to any degree of rash than were men. 
When any rash (from mild to severe) was counted, about 16 percent of women
and 8 percent of men were affected. Two women and two men experienced
Stevens-Johnson syndrome, a life-threatening form of severe rash in which
large sheets of skin die and peel off. Because of the smaller number of
women treated with nevirapine, the two cases represent a larger proportion
of women with Stevens-Johnson syndrome than men. There were apparently no
deaths reported due to nevirapine in this sample. The incidences of elevated
liver enzymes and liver disease were not collected. 
While the sex of the patient was strongly associated with the development of
severe rash in this study, other possible factors were also identified.
Individuals with higher CD4 counts when starting nevirapine tended to have
more episodes of severe rash and had to stop therapy due to rash more often.
Patients younger than 35 years tended to discontinue nevirapine more often
than older patients but did not have significantly more cases of severe
rash. Of 23 women who took birth control hormones, 4 (17%) experienced
severe rash compared to 5 of 72 (7%) women not taking contraceptive
hormones. In this population, 76 percent of the women were African-American
compared with 43 percent of the men. The authors report, however, that no
association was observed between race and the incidence of rash in the
study.
Rash Decisions
Although the key clinical trials that led to the approval of nevirapine
uncovered a risk of having skin reactions when starting the drug, none of
those studies examined the differential risk between men and women. One
company-sponsored report also presented at the Glasgow conference last year
described an early, large (2,249 patient) trial comparing nevirapine with
placebo. The authors reported an equal incidence of elevated liver enzymes
in each comparison arm and a greater number of liver-related deaths in the
placebo arm. Overall, women comprised 20 percent of that study population
although, once again, the adverse event rates for men and women were not
reported separately.11
There is a small amount of provocative evidence that women may experience
more adverse reactions to medications in general. Though not HIV-specific,
two surveys of hospital inpatients performed in the 1970s and 1980s found a
generally increased risk of drug-related skin reactions among women,
reporting an incidence in women 35 to 50 percent higher than in men.12,13
But the authors of the nevirapine sex differences study caution that, while
the differences they found in the incidence of severe rash between men and
women are statistically significant, the overall number of episodes of rash
in their study are small and could possibly be due to other, unexamined,
factors. Another limitation of the study is that the observations were not
pre-planned but were collected from medical records after the fact.
Retrospective studies of this sort can contain undetected biases if, for
example, different staging systems for rash were used at different times or
at different sites. One limitation in particular is a lack of information
about any additional medications patients may have been taking while they
were receiving nevirapine. 
Despite these caveats, the authors conclude, it is at least safe to say that
the risk of nevirapine rash cannot simply be extrapolated between sexes, as
is commonly done. This is a particular problem since our knowledge of
adverse reaction rates is drawn from study populations with small
proportions of women. As demonstrated by the sex-differences study, overall
incidence rates of rash may be similar to the rates for men, but rates for
women may appear dramatically higher when they are isolated. Since no
previously published study of nevirapine has differentiated adverse reaction
rates by sex, clinicians and patients have no choice but to judge expected
rash episodes by published overall incidence rates or by anecdotal
experience.
Although most nevirapine-associated deaths have been liver-related, the
sex-differences study only reported on the relative incidence of rash. Yet,
mild to moderate rash may be one of the warning symptoms of liver disease.
In the South African FTC trial, rash was temporally associated with Grade 4
liver enzyme elevation in 25 percent of cases. If this association is
common, then an increased incidence of rash may possibly warn of an
increased risk for liver disease among women starting nevirapine.
Compounding the risk for black women, it's been suggested that the
appearance of rash on darker skin may be more difficult to diagnose than on
lighter skin.14 Add to this an increasing trend among physicians to "treat
through" mild nevirapine rash when initiating therapy, and the need for
close clinical management and frequent monitoring of liver enzymes becomes
crucial. 
The evidence of sex differences in the incidence of drug-associated rash and
liver disease suggests that women, with whom most U.S. clinicians probably
have less overall experience, need vigilant monitoring and extra counseling
about possible treatment-associated adverse events - including rash - when
initiating an antiretroviral regimen containing nevirapine.
Footnotes:
1. Guay LA, et al. Intrapartum and neonatal single-dose nevirapine compared
with zidovudine for prevention of mother-to-child transmission of HIV-1 in
Kampala, Uganda: HIVNET 012 randomized trial. The Lancet. 1999 254:795-802.
2. Moodley D, et al. Evaluation of safety and efficacy of two simple
regimens for the prevention of mother to child transmission (MTCT) of HIV
infection: nevirapine vs lamivudine and zidovudine used in a randomised
clinical trial (the SAINT study). (Abstract TuOrB356) XIII International
AIDS Conference, Durban, South Africa, July 9-14, 2000. 
3. Sanne I, et al. Severe liver toxicity in patients receiving two
nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor.
(Abstract) Fifth International Congress on Drug Therapy in HIV Infection,
Glasgow, UK. AIDS. 2000;14(supplement):PL 9.3.
4. Sha BE, et al. Adverse effects associated with use of nevirapine in HIV
postexposure prophylaxis for 2 health care workers. (Research Letter) JAMA.
2000;284:21.
5 . Henderson D. Post-exposure prophylaxis. (Abstract) Fifth International
Congress on Drug Therapy in HIV Infection, Glasgow, UK. AIDS.
2000;14(supplement):PL 6.1.
6. Johnson S, et al. Adverse effects associated with use of nevirapine in
HIV postexposure prophylaxis for 2 health care workers. (Research Letter)
JAMA. 2000;284:21.
7. Centers for Disease Control and Prevention (CDC). Serious adverse events
attributed to nevirapine regimens for postexposure prophylaxis after HIV
exposures - Worldwide, 1997-2000. MMWR. 2001 Jan 5.
8. European Agency for the Evaluation of Medicinal Products. EMEA Public
Statement on Viramune. April 2000; EMEA/11260/00.
9. Roxane Laboratories. Important Drug Warning Re: Severe, life-threatening
and fatal cases of hepatotoxicity with Viramune. November 2000.
10. Bersoff-Matcha SJ, et al. Sex Differences in Nevirapine Rash. Clinical
Infectious Diseases. 2001;32:124-9. (This study was first presented as a
poster at the 6th Conference on Retroviruses and Opportunistic Infections in
1999).
11. Cahn P, et al. Hepatic safety with nevirapine (NVP) and two nucleosides
in patients with advanced HIV infection, from a placebo (PBO) controlled
clinical endpoint trial (1090). (Abstract) Fifth International Congress on
Drug Therapy in HIV Infection, Glasgow, UK. AIDS. 2000;14(supplement):PL 8.6
12. Arndt KA, Jick H. Rates of cutaneous reactions to drugs: a report from
the Boston Collaborative Drug Surveillance Program. JAMA. 1976;235:918-22.
13. Bugby M, et al. Drug induced cutaneous reactions: a report from the
Boston Collaborative Drug Surveillance Program on 15,438 consecutive
inpatients. JAMA. 1986;256:3358-63.
14. Gilden D. Liver Failures Spark Nevirapine Warning. (Statement by Franck
Rosseau, V.P. for Medical Affairs, Triangle Pharmaceuticals, sponsor of the
FTC trial). The amfAR Treatment Insider. August 2000;1(4).

But is it really, really safe?
Although no severe rashes or liver problems have been reported for
single-dose nevirapine given to pregnant women, the original Phase I study
of nevirapine in pregnant women may be worth taking a closer look at. In a
trial conducted at seven hospitals in the United States and Puerto Rico,
seventeen women in active labor were given single doses of nevirapine
(either 100 mg or 200 mg) when they arrived at the hospital. The women had
previously been enrolled in the study and were receiving a standard course
of zidovudine to prevent HIV transmission to their infants. Blood samples
were drawn at frequent intervals after the nevirapine dose and daily after
delivery. The levels of nevirapine in the blood samples were charted to find
the peak concentration and the rate of clearance from the body. 
Nevirapine has a relatively long life in the blood (ideal for preventing
mother-to-child transmission) but the amount of time nevirapine remained in
the bodies of these pregnant women varied dramatically - both between the
women on the study and from historical data in men and non-pregnant women.
One woman, who received a 100 mg dose, still had more than half the
nevirapine in her blood after seven days. Considering that one of the
needle-stick victims who started prophylactic nevirapine (see 'PEP
Tragedies') developed symptoms within 8 days, it's not unimaginable that
there may eventually be a rare adverse event resulting from single-dose
nevirapine. Yet, this scenario is highly unlikely because, as in the
needle-stick case, symptoms have only developed after several consecutive
days of daily dosing. 
If nevirapine is slower to clear from women's bodies, whether pregnant or
not, then the increased incidence of rash and liver problems among women on
daily-dosing regimens may be due to a gradual accumulation of the drug to
toxic levels. The wide variability of drug concentrations seen in pregnant
women and reports of slower clearance of nevirapine from non-pregnant women
point to the need for additional pharmacokinetic studies of nevirapine in
women. 
Footnotes:
Mirochnick M, et al. Pharmacokinetics of Nevirapine in Human Immnodeficiency
Virus Type 1-Infected Pregnant Women and Their Neonates. Journal of
Infectious Diseases. 1998;178:368-74.
Lamson MJ, et al. Effects of gender on the single and multiple dose
pharmacokinetics of nevirapine. Pharm Res. 1995; 12:S-101.
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