Management of Antiretroviral Toxicities and HCV Coinfection

[Guest guest]

Medscape coverage of: 46th Annual Interscience Conference on Antimicrobial

Agents and Chemotherapy | ICAAC 2006 - HIV Infection: Antiretroviral

Strategies, Management of Adverse Effects, Treatment of HCV Coinfection

ICAAC 2006 - Management of Antiretroviral Toxicities and HCV Coinfection

CME

Disclosures

Ward, MD

Introduction

The optimal management of common HIV-associated coinfections and the adverse

effects of antiretroviral therapy is one of the most important concerns for

all HIV clinicians. Indeed, beyond achieving a favorable virologic and

immunologic response to antiretroviral therapy for HIV, a beneficial

long-term outcome often rests upon finding a safe, well-tolerated regimen.

Furthermore, preventing liver disease associated with viral hepatitis has

emerged as one of the key challenges in HIV medicine. New data from the 46th

ICAAC provided a few new insights into how to achieve the equilibrium

between efficacy and safety as well as emerging approaches to the management

of hepatitis C in persons with HIV.

Lipoatrophy: Prevention Remains the Best Option

For patients who are virologically well controlled on an antiretroviral

regimen, the risk for lipodystrophy is a significant concern. Lipoatrophy,

or the loss of subcutaneous fat, has been associated with use of nucleoside

reverse transcriptase inhibitors (NRTIs), particularly thymidine NRTIs; but

the incidence of this complication seems to have declined as the use of

other, less toxic NRTIs has increased. Treatments to reverse lipoatrophy,

however, have not shown significant success. MacCallan and colleagues[1]

reported a comparison of some interventions that have been tried, including

statins, glitazones, and recombinant human growth hormone (rHGH). Sixty

patients with HIV-associated lipoatrophy were randomized to treatment for 12

weeks with pravastatin, rosiglitazone, pravastatin + rosiglitazone, or to

treatment for 12 weeks with rHGH (at a low dose of 2 mg/day for 12 weeks),

or rHGH + rosiglitazone. Patients were assessed every 12 weeks by DEXA and

CT scans, anthropometrics, and biochemical analyses.

At 48 weeks, neither rosiglitazone nor pravastatin, alone or in combination,

showed any benefit against lipoatrophy. rHGH showed a significant decrease

in abdominal fat and increase in abdominal and limb lean tissue at 12 weeks,

but this reversed on discontinuation of rHGH. Furthermore, rHGH also

decreased limb fat. Rosiglitazone reversed the insulin resistance that is

commonly associated with rHGH. These results are consistent with the

frequently observed shortfalls to interventions that might reverse

lipoatrophy. As with many other medical problems, the best intervention that

we have is prevention of the condition.

Nevirapine and Abacavir: Analyzing the Risk for Hepatotoxicity, Rash, and

Hypersensitivity Reactions

Nevirapine. Abacavir and nevirapine are 2 potent, generally well-tolerated

drugs whose use is complicated by the risk for hypersensitivity reactions

(HSR) at the initiation of therapy. The risk for liver toxicity to

nevirapine is related to gender and immune status, and is usually considered

to be unacceptably high in men and women with CD4+ cell counts over 400 and

250 cells/mcL, respectively. However, in a retrospective review of more than

500 patients initiating nevirapine, Wolf and associates[2] analyzed factors

associated with grade 3-4 elevation of alanine transaminase (ALT). While

baseline liver function test elevations and chronic hepatitis B or C were

statistically associated with liver toxicity, there was no significant

association observed with higher CD4+ cell counts or female sex.

In a related analysis, De Lazzari and others[3] looked at the risk of liver

toxicity or rash in virologically controlled patients on treatment who

switched to nevirapine. In this retrospective study, patients were divided

into 2 CD4+ cell count strata:

High CD4 stratum (¡Ý 400 cells/mcL for men, ¡Ý 250 cells/mcL for women)

Low CD4 stratum (< 400 cells/mcL for men, < 250 cells/mcL for women)

A total of 410 patients were included: 133 in the low-stratum and 277 in the

high-stratum group. Liver toxicity occurred in 2% and 4% of patients in

these groups, respectively. While liver toxicity still existed in this

treatment-experienced population, it occurred at a substantially lower rate

than what was seen in treatment-naive patients. The odds ratio for toxicity

with higher CD4+ cell counts was 1.46, which was not statistically

significant. The only factor associated with risk for liver toxicity that

was found in this group was baseline elevation of liver function tests;

higher CD4+ cell counts and female sex did not appear to be risk factors in

this treatment-experienced population.

The risk for potentially serious toxicity when initiating therapy with

nevirapine is significant, and this drug needs to be used with caution in

patients with higher CD4+ cell counts.[4] These data suggest, however, that

perhaps there is a need for further analysis of the data, and in particular,

those patients already virologically suppressed who are switching to

nevirapine may have a lower risk for toxicity.

Abacavir. Abacavir is another commonly used antiretroviral drug with a risk

for HSR, which can be severe. In multiple studies, the overall risk for this

reaction is approximately 5%, and many experts believe that HSR risk

correlates to host genetic factors. Brothers and colleagues[5] reported a

retrospective review of the incidence of reported cases of HSR by race in 5

large clinical trials in which abacavir was tested. Among 2800 patients in

these trials, the incidence of HSR in blacks ranged from 2.3% to 5.7%, which

was approximately half the incidence in the overall population (range: 5.3%

to 8.3%). The decreased incidence, however, does not eliminate the need for

patient counseling before starting abacavir.

This observation is consistent with the known association of the HSR with

the HLA genotype B*5701,[6] which is less common in persons of African

descent. The observed association with HLA B*5701 is significant, and many

experts now recommend screening for this genotype before initiating therapy

with abacavir. Unfortunately, the test is of limited availability, quite

expensive, and can take weeks to receive results.

In an effort to overcome these limitations, Harrigan and associates[7] from

the British Columbia Center for HIV/AIDS reported a simple screening

approach to reduce the risk for abacavir HSR. As background, HLA antigens

combine with HIV peptides to form the epitope that is recognized by

cytotoxic T lymphocytes (CTL). Because CTL responses are preferentially

associated with HLA haplotypes, this is a major force shaping viral mutation

via CTL escape. HIV reverse transcriptase codon 245 is in a known

HLA-restricted region, and mutations at this site represent a response to

selective pressure by CTL. Codon 245 is in the region that is sequenced in

genotypic resistance testing, so mutations at this site can be characterized

by genotypic assays. Harrigan reported an analysis of 392 patients who

initiated abacavir therapy and who had a pre-treatment HIV genotype and

blood available for HLA typing. At baseline, only 1 of 279 patients who were

wild-type at locus 245 of HIV were positive for B*5701, the haplotype

associated with ABC HSR. In contrast, 23 of 90 with substitutions at this

locus were positive. This was a highly significant result and had a negative

predictive value of 99.6%. In a larger group of patients initiating abacavir

therapy, mutations at the 245 locus were statistically associated with

discontinuation of abacavir within 3 months (P < .02).

Although not definitive, this test, which uses information already available

for many patients beginning therapy, may be a useful screen for HLA B*5701,

and therefore may help predict the risk for abacavir HSR. Wild type at this

locus is strongly associated with lack of B*5701, while mutations at the

locus may be an indication to actually obtain HLA typing.

Management Advances for Patients With Hepatitis C Virus Coinfection

Coinfection with hepatitis C virus (HCV) remains a significant complication

associated with HIV infection. The APRICOT trial[8] showed that treatment

with pegylated interferon and ribavirin can result in sustained virologic

response, even in patients with HIV coinfection. Two presentations at the

46th ICAAC looked at predictive factors for successful treatment of HCV,

based on analysis of APRICOT. - and others[9] looked at

baseline HCV viral load as a predictive factor, and found that those with

viral loads < 400,000 IU/mL had a likelihood of sustained virologic response

(SVR) of > 70%, regardless of HCV genotype. In those with viral loads >

400,000 IU/mL, the likelihood of response was significantly lower in those

patients with genotype 1; the difference in response was less substantial

among patients with genotypes 2 or 3 and viral load > 400,000. A similar

pattern has previously been shown in relation to baseline CD4+ cell count:

With genotype 1, the probability of successful treatment is related this

parameter, although this relationship is not seen with genotypes 2 or 3.

Dieterich and associates[10] analyzed the effect of CD4+ cell percentage on

response to peg-IFN + ribavirin and found similar associations. With

genotype 1, those with a CD4% of < 19.1% had a 16% SVR, whereas those with a

CD4% >32.1% had 27% SVR In genotypes 2 or 3, there was no significant

difference among the 4 CD4% quartiles that were examined.

Two other presentations looked at treatment of hepatitis C in special

populations of HIV-coinfected patients. There have been anecdotal reports

that treating hepatitis C during the first year after infection has a higher

probability of SVR, even in HIV-coinfected patients. Vogel and others[11]

evaluated outcomes in 40 patients with documented HCV infection within 4

months of diagnosis. A total of 26 patients had HCV genotype 1, and median

HCV viral load and CD4+ cell count were 700,000 IU/mL and 440 cells/mcL,

respectively. Ten patients declined treatment; 7 of those progressed to

chronic hepatitis. Thirty patients were treated with peg-IFN for 24 weeks; 8

patients extended treatment to 48 weeks, and treatment was discontinued

early in 4 patients. By intent-to-treat analysis, 73% (22/30) of patients

had a virologic response at end of treatment, which was sustained in 63%

(19/30). This is an impressive response rate and suggests that early

treatment has a greater chance of success.

Labarga and coworkers[12] looked at patients at the other end of the

treatment spectrum -- those who had already failed HCV therapy. Fifty-one

patients who had previously either failed to respond or relapsed after

treatment with interferon monotherapy, interferon + ribavirin, or peg-IFN +

ribavirin were re-treated with peg-IFN 180 mcg weekly + daily treatment with

ribavirin based on weight (< 75 mg: 1000 mg; > 75 kg: 1200 mg).

Seventy-seven percent of patients achieved an early virologic response

(greater than 2-log10 decrease in HCV viral load at 12 weeks). Success rate

was higher in those with genotype 3 (100%) than in genotypes 1 or 4 (67% and

80%, respectively). The success rate was also higher in previous relapsers

than in previous nonresponders, in patients previously treated with

interferon monotherapy compared with patients previously treated with

interferon + ribavirin, and in those with lower levels of liver fibrosis.

Although further study is needed, these early results hold promise:

Re-treatment of HCV after a treatment failure may be less futile than we

presume.

References<cut>

http://www.medscape.com/viewarticle/546699?src=mp

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