Antiretroviral therapy in co-infected individuals

On the whole, antiretroviral therapy is safe and effective in HIV/HCV co-infected people. However, several studies have shown that the risk of liver toxicity related to anti-HIV drugs is greater among people with viral hepatitis. This is partly due to existing liver damage from chronic hepatitis infection.

In addition, as antiretroviral therapy improves immune function, this can lead to a form of immune reconstitution syndrome characterised by transient flares of liver inflammation and elevated liver enzymes as the immune system steps up its attack against HCV in liver cells.¹ This condition is most likely to develop when people respond well to HIV treatment, with a CD4 cell count increase of 50 cells/mm³ or more. If hepatitis flares up, antiretroviral therapy may need to be suspended temporarily to address the hepatitis.

There is evidence that those with HIV/HCV co-infection are at significantly lower risk of elevated cholesterol and lipodystrophy, compared to HIV-positive patients without HCV; there are conflicting results as to how and whether co-infection affects the risk of diabetes.^{2 3 4 5 6}  HCV genotype 3 may exert a stronger cholesterol-protective effect than other HCV genotypes.

While certain anti-HIV drugs are also active against HBV, they do not have a direct effect on HCV.⁷ HAART has been associated with a significant transient rise in HCV viral load.^{8 9}  This is particularly the case in people who had a baseline CD4 cell count below 350 cells/mm³ and greater HCV viral diversity. The clinical implications of this increase in HCV viral load are unknown, although it may play a part in liver damage in the short term.

In reports from two Spanish studies presented in early 2008, co-infected patients who were receiving tenofovir (versus abacavir) had the best chances of sustained virological response to HCV therapy.

In a retrospective multicentre study of 256 patients who started first-line HCV therapy with pegylated interferon (peg-IFN) and ribavirin while receiving three-drug ART for HIV infection, a significantly better responses to HCV therapy were seen with tenofovir than with abacavir. Lower SVR in patients taking abacavir was most pronounced and significant in those who received lower ribavirin doses; at higher doses, the trend remained but became statistically insignificant.¹⁰

In a second, larger study over 700 patients initiating first-line HCV therapy, concomitant ART therapy consisted of dual NRTIs plus an NNRTI or a PI or triple-nucleoside therapy including abacavir. Again, tenofovir was associated with better-sustained virologic responses to first-line HCV treatment; however, researchers concluded that AZT (and not abacavir) was associated with poorer tolerability and efficacy. There was not, in this study, a significantly different outcome for patients on dual nucleoside therapy including abacavir.¹¹

In this study, an unspecified number of patients on abacavir-containing triple-nucleoside therapy were grouped with the other patients on AZT, not abacavir; and change of ART was considered as treatment failure. Further, prospective studies may be needed to distinguish the impact of AZT and abacavir on pegylated interferon/ribavirin treatment for HCV.

In the long term, research clearly shows that the benefits of anti-HIV therapy outweigh the risks. Some studies have shown that HAART is associated with slower progression to fibrosis and cirrhosis, although one Spanish study found that antiretroviral therapy neither slowed nor accelerated the development of fibrosis.^{12 13 14} A small Spanish retrospective analysis of 199 patients showed that antiretroviral therapy in people with CD4 counts above 350 was associated with less fibrosis during four years of follow-up.¹⁵

Furthermore, another Spanish study of 248 co-infected patients has shown that people with more advanced liver disease - compensated cirrhosis or advanced cirrhosis - were less likely to progress to decompensated cirrhosis and less likely to die if they received continuous antiretroviral therapy (74% of this population were non-responders to hepatitis C treatment).¹⁶

HIV therapy is also associated with a lower rate of mortality due to liver-related causes in co-infected individuals according to a German study published in The Lancet .¹⁷ For HIV/HCV co-infected patients, stated an accompanying editorial, the risks of hepatotoxicity, although real, should not diminish the use of HAART, but should encourage more widespread use of pharmacokinetic testing and development of new agents against HIV-1 that have less effect on liver metabolism.¹⁸ Atazanavir (Reyataz), for instance, has been found to be safe and effective in co-infected patients with cirrhosis.¹⁹

Antiretroviral treatment interruption has been found to be particularly unsafe in people with HCV or HBV co-infection. In the large SMART study of treatment interruption, while OI rates were similar with and without HCV, co-infected people who interrupted treatment were far more likely to die of liver or kidney disease or other, unknown causes.^{20 16}

Most studies show that antiretroviral therapy is effective in HIV/HCV co-infected individuals, although most have a slower or blunted CD4 cell count increase after starting HAART.^{21 22 23 24} The reason is unknown, but experts have suggested that HCV may alter production or programmed cell death of T-cells,that it may be due to lower IL-7 levels, or that there may be a biological interaction between HIV treatment and the hepatitis C virus. Other factors may contribute, such as the need for treatment interruptions in co-infected patients and the adherence difficulties experienced by some injecting drug users, who make up a large proportion of co-infected patients.²⁵ Interferon-based HCV therapy can also lead to an overall decline in white blood cells, although this would not affect the CD4 cell percentage.

However the largest analysis to date, involving more than 4000 patients in the EuroSida cohort, failed to detect any difference in the rate of CD4 cell restoration on HAART, and no effect of hepatitis C viral load on CD4 cell restoration.²⁶

Virological response to HIV therapy has generally been found to be unaffected or slightly decreased by HCV co-infection, although one study suggested that HCV co-infection was weakly associated with HIV treatment failure.²⁷  This is, as yet, an isolated finding.

In a recent Italian study, HCV viral load (detectable HCV RNA) was associated with poorer immune response to HAART, suggesting that successful anti-HCV therapy might facilitate anti-HIV treatment.²⁸

Other studies have not found a difference in immunological recovery, however, and a recent Thai study found that the early delay in CD4 T-cell recovery did not last, and was not associated with increased HIV disease progression.^{29 30 31}

Among the total HIV-positive population, about 3 to 4% of individuals develop acute liver disease within two years of starting HAART.³² Hepatitis C co-infection has been shown to increase the risk of liver toxicity, characterised by an increase in liver enzyme levels after starting antiretroviral drugs. This can include serious grade 4 liver toxicities.^33,34 Not surprisingly, the chances of drug-related liver toxicity are highest in individuals who already have advanced liver damage.³⁵

In an Italian study, 26 cases of life-threatening liver disease (seven of them fatal) occurred among 755 people after they commenced HAART. Sixteen individuals received liver biopsies, which showed evidence of exacerbation of chronic active hepatitis, but no signs of drug-related hypersensitivity damage. Following a treatment interruption (which in some cases included a course of interferon), the 19 survivors successfully recommenced HAART without recurrence of acute liver disease.³⁶ Small studies have also suggested a link between use of fosamprenavir (Telzir) and liver toxicity in HCV-co-infected patients,³⁷ as well as reduced lopinavir and elevated efavirenz levels.³⁸

In addition to HCV co-infection, several other factors have been linked to liver toxicity among people starting HAART, including alcohol consumption, injection drug use, age over 35, hepatitis B or D co-infection, elevated liver enzymes at baseline, and good response to therapy.^1,32 The largest study to date has found an 8.7% incidence rate of liver toxicity in co-infected patients starting HAART, and identified the following as the largest risk factors: elevated baseline liver enzymes, bilirubin or creatinine levels, low baseline WBC or platelet counts, or use of hepatotoxic medications including nevirapine. However, these data were gathered during the 1990s and reflect the treatments in use at that time.

Although many anti-HIV medications have occasionally been linked to liver problems, liver toxicity has most often been associated with protease inhibitors as a class.³⁹ This has particularly been seen with full-dose ritonavir (Norvir), although not all studies show this association, and full-dose ritonavir is now essentially never used. The lower ritonavir doses used to boost other protease inhibitors are less likely to cause liver problems. Ritonavir-boosted lopinavir (Kaletra) has also been linked to severe liver enzyme elevations, especially in individuals co-infected with HBV or HCV but other studies have yielded low liver toxicity rates.^40,41,42

The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune) can cause a hypersensitivity reaction characterized by liver damage and skin rash, and has also been associated with faster fibrosis progression.⁴³ In January 2005, the FDA issued a public health advisory confirming that nevirapine can cause potentially life-threatening liver toxicity, especially in women and in patients with higher pre-treatment CD4 cell counts (above 250 cells/mm³ for women and above 400 cells/mm³ for men). One study has found that, among people who develop this nevirapine hypersensitivity reaction, the risk of death was seven times higher in co-infected than in people without HCV.

One study has found that people with HCV or HBV are not at increased risk of liver toxicity when taking nevirapine or efavirenz (Sustiva).⁴⁴

Importantly, the absolute rate of serious side-effects associated with antiretroviral drugs remains quite low.^45,44 A Canadian study, for example, found that just 7% of co-infected patients developed an ALT level more than five times the upper limit of normal, and only 3% switched or discontinued anti-HIV medications due to liver problems, all of whom were taking full-dose protease inhibitors.

Due to the increased risk of liver toxicity, co-infection may influence the choice of anti-HIV drugs. Ideally, care of co-infected individuals should be managed by clinicians who have experience with both diseases, and regular monitoring of liver function is recommended when co-infected people start HAART or change antiretroviral drugs.

Studies are beginning to suggest that HCV co-infection itself is a significantly greater risk for liver toxicity than HAART itself³⁵ and that HCV genotype 3 is a particular risk for liver toxicity for co-infected patients on HAART.⁴⁶