HCV/HIV coinfection guidelines may lead to unnecessarily premature HAART discontinuation

Current HIV/hepatitis C (HCV) guidelines suggesting highly active antiretroviral therapy (HAART) discontinuation when liver function tests suggest grade III/IV toxicity may lead to unnecessarily premature HAART discontinuation, according to research published in the 15^th October edition of Clinical Infectious Diseases, now available online. Researchers from the University of Cincinnati, Ohio, found that although HCV viral load and ALT levels flared during HAART, they returned to baseline by week 48, and allowed HIV/HCV coinfected patients to benefit from continued, sustained HIV load reductions and substantial immune reconstitution.

Previous studies have found a paradoxical increase of HCV viral loads following initiation of HAART, which were transient in some cohorts and more persistent in others. Consequently, investigators from the United States sought to evaluate the impact of two specific protease inhibitor (PI)-based HAART regimens - nelfinavir (Viracept) or lopinavir/r (Kaletra) with 3TC (lamivudine, Epivir) and d4T (stavudine, Zerit) - on liver function tests and HCV viral loads in coinfected, antiretroviral-naive patients enrolled in a prospective, randomised trial.

The parent study enrolled 653 participants from 93 centres in 13 countries. Inclusion criteria included an HIV viral load of at least 400 copies/ml and no prior treatment with 3TC or d4T, although previous experience with other antiretrovirals more than 14 days prior to enrolment was allowed. Exclusion criteria included ALT and AST levels three times the upper the limit of normal or greater.

A total of 70 (11%) participants tested HCV antibody positive. There were no demographic differences seen between this sub-group and the rest of the cohort. Of the 70 with HCV antibodies, the majority were male, white, and acquired HIV through injecting drug use. Twenty-nine had been randomised to receive Kaletra and 41 received nelfinavir. Of the 70, 57 (81%) had quantifiable HCV viral loads, suggesting that the other 19% had cleared the virus.

A total of six participants in each arm dropped out of the study prior to completion. There were no statistically significant differences between the two treatment arms regarding the reasons for discontinuation, and rates of discontinuation associated with specific causes did not differ greatly.

HIV viral load and CD4 responses

Both treatment arms sustained dramatic reductions in HIV viral load by week 48: 100% of those still on treatment achieved less than 50 copies/ml on Kaletra compared with 73% of those on nelfinavir (p=0.308). There were also no statistically significant differences seen between coinfected and monoinfected participants in terms of virological or immunological response.

Within the coinfected cohort, however, there was a statistically significant difference seen in CD4 increases, but only in those participants who had less than 100 CD4 cells/mm³ at baseline: 221 cells/mm³ versus 147 cells/mm³ (p=0.049).

HCV viral load response

Mean HCV viral loads increased in the coinfected cohort after HAART initiation. By week 24 they had increased by 6.1% and 9.6% from baseline but by week 48, they had reduced to 1.1% and 8% above baseline in participants on Kaletra and nelfinavir, respectively.

In the subset of coinfected participants with CD4 counts below 100 cells/ mm³, however, much more marked differences were seen between those on Kaletra and nelfinavir. Participants on Kaletra had mean 6.4% increases of HCV viral load from baseline at week 24, but 5.2% decreases from baseline at week 48. In contrast, participants on nelfinavir had mean 23.3% increases of HCV viral load from baseline at week 24, and 26.5% increases from baseline at week 48.

In fact, five of eleven nelfinavir-treated coinfected patients with CD4 counts below 100 CD4 cells/mm³ at baseline experienced an increase of HCV viral load from baseline of more than 0.5 log at week 48, compared with none of the ten on Kaletra.

Liver damage

ALT levels were used as a surrogate marker of liver damage. At baseline no statistically significant differences were seen between the two treatment arms, but at week 24 those on nelfinavir-based HAART experienced 111.4% increases from baseline, whereas those on Kaletra-based HAART experienced a 5.5% decrease from baseline. However, after 48 weeks of therapy, the mean ALT levels in both treatment arms did not differ significantly from baseline levels.

Using grading for ALT levels, eight (19.5%) coinfected participants on nelfinavir and two (6.9%) on Kaletra had grade III or IV ALT-related adverse events (p=0.18). The pattern of ALT flares tended to occur later among those on Kaletra compared with those on nelfinavir (hazard ratio 2.93; 95% CI, 0.62-13.8).

Conclusions

The researchers argue that "ALT increases after the initiation of HAART may lead to antiretroviral drug discontinuation or dose modification" based on current coinfection guidelines. "In our cohort," they add, "application of these rules might have significantly altered treatment regimens. Although clinical outcomes were not significantly different between these two regimens after 48 weeks, clinicians seeing flares in ALT level and/or HCV loads might have altered their choice of treatment regimen at the time of the flare, resulting in suboptimal therapeutic efficacy."

They concede that there were limitations to this study that may limit its generalizability. The parent cohort included a higher proportion of gay men relative to the general coinfected population, and rate of coinfection (11%) is lower than seen in other cohorts with greater proportions of injecting drug users. HCV viral load was only measured at three timepoints (baseline, weeks 24 and 48) unless a flare in ALT levels was noted. This limited the researchers' ability to correlate HCV viral loads with ALT levels and CD4 counts over time.

However, the researchers say that their "analysis confirms that HCV loads increase after HAART initiation and that this increase is associated with appropriate immune reconstitution." They add that patients with low CD4 counts experience different antiretroviral effects on HCV viral loads and ALT levels, making initial treatment choices that limit HCV viral load and ALT level flares in this population of paramount importance, and conclude by suggesting that further studies "should include histological evaluation at the time of flare, so that the level of liver injury in this setting can be assessed."