Project Inform - September, 1998

Hepatitis C

Confusion remains regarding the advisability of using protease inhibitors in people co-infected with HIV and hepatitis C virus (HCV). This concern arises because most of the protease inhibitors place some degree of strain on the liver, which is greatly stressed by HCV. One recent study suggests that people co-infected with HIV and HCV who start on a protease inhibitor-containing regimen may be at greater risk of developing cirrhosis, a potentially life-threatening liver disease. This study also found that people generally had higher HCV levels (as measured by a special version of PCR test) after starting a protease inhibitor and these levels remained elevated throughout the duration of therapy. There was no apparent correlation between pre-therapy HCV levels and the impact of protease inhibitor therapy on liver disease. This means that people with low HCV levels prior to initiating therapy were just as likely to develop active symptoms of liver disease as people with high pre-therapy HCV levels. Thus, people with low pre-therapy levels could not be assured that they could safely use protease inhibitor therapy. However, another study contradicts these findings. This second study found that although protease inhibitors appeared to increase HCV levels and liver enzymes, this was transient and lasted only a few weeks. In longer-term follow-up (over 2 years), people were able to use the protease inhibitors safely with no effect on HCV levels or liver enzymes.

Another study that looked at historical medical records observed that people who were co-infected with HIV and HCV did not respond as well to anti-HIV therapy compared to people who were not HCV infected. Compared to their pre-therapy levels, those co-infected tended to have increased HIV RNA levels and decreased CD4+ cell counts whereas people who were not HCV infected had decreases in HIV RNA and increase in CD4+ cell counts. In this sense, the presence of HCV infection could be considered a co-factor which stimulated the activity of HIV. Because this study simply looked back at medical records it is difficult to interpret whether these HIV drug failures can be directly attributable to HCV infection or if there were other factors contributing to the differences between the two groups.

On a positive note, a treatment study found that people co-infected with HCV and HIV responded equally well to interferon-alfa, a treatment for hepatitis C, compared to HCV infected individuals who are not HIV-infected. This is contrary to the experience of people co-infected with HIV and hepatitis B virus who usually do not respond well to interferon treatment. Study participants received thrice weekly injections of interferon-alfa (3 million units) for three months. Those who responded to therapy continued for another 9 months. This study found that both HIV infected and HIV negative individuals had similar decreases in HCV RNA levels and normalization in liver enzyme tests, with approximately 25% of both groups having a sustained response past one year of therapy. However, people who were co-infected and had HCV levels over 10,000,000 copies or a CD4+ cell count below 500 were less likely to have a response. It should be noted, however, that treatment with interferon-alfa alone is no longer considered state of the art treatment for hepatitis C. The FDA recently approved a treatment which combines interferon-alfa with the broad-spectrum antiviral drug ribavirin (Rebetol^®) and is marketed as a combination known as Rebetron^®. Ribavirin was previously studied for use in HIV disease. This combination appears to be far more effective than single drug therapy for HCV. People who are co-infected with HIV and HCV should be aware that use of this new recommended treatment for HCV infection can cause some interactions with anti-HIV therapies. In particular, the use of ribavirin tends to increase the potency of ddI several fold. Ribavirin also has an interaction with AZT which results in decreased anti-HIV activity of AZT.

Mycobacterial Infection

Results from a recent study show that the addition of rifabutin (Mycobutin^®) to a standard anti-mycobacterium avium complex (MAC) regimen of clarithromycin (Biaxin^®) and ethambutol (Myambutol^®) resulted in no additional benefit in reducing symptoms of MAC disease, but may prevent the development of clarithromycin-resistant MAC. This is important as clarithromycin is considered the most active drug against MAC; but once resistance to this drug sets in, a patient's ability to combat MAC is dramatically reduced. Almost 200 people with active MAC participated in this study and received clarithromycin + ethambutol +/- rifabutin. At the end of the 16 week study, there were no differences in reduction of MAC colony forming units (a measure of the amount of MAC found in blood), rate of relapse, symptoms of MAC disease or survival between the two groups. However, of those who relapsed and again developed active MAC, only one person who had previously received the 3-drug combination developed resistance, whereas six who had received the 2-drug regimen developed clarithromycin-resistant MAC. While the addition of rifabutin might not result in a long-term benefit, it may be able to delay or prevent the emergence of clarithromycin-resistant MAC.

Stopping Therapy

There have been many anecdotal reports of people stopping prevention and maintenance (to prevent relapse of an infection) therapies for opportunistic infections after getting a good virologic and immunologic response from HAART. Results from a few studies offer some guidance on who might be able to successfully stop OI therapy.

A Swiss study enrolled 230 people whose CD4+ cell counts rose and remained above 200 and sustained a 14% total lymphocyte count for at least three months prior to stopping their PCP preventative therapy. After 12 weeks of follow up, there have been no cases of PCP. However, given the short follow-up time, it may be premature to make conclusive recommendations about stopping the use of PCP preventative therapies.

In a study designed to examine cytomegalovirus (CMV)-specific immune responses in people stopping CMV retinitis maintenance therapy, it was found that 9/13 people developed vitritis (an inflammation in the eye) in the same eye as that of the retinitis. The vitritis was associated with decreased vision and led to blindness in some people. In general, people developed vitritis about 3 months after stopping CMV maintenance therapy and there was no evidence of re-emergence of the retinitis. Interestingly, people who had higher CD4+ cell count increases and stronger immune responses specific to cytomegalovirus were more likely to develop vitritis. The researchers believe that ironically people with stronger immune systems are still responding to residual cytomegalovirus in the eye and thus are experiencing this inflammatory response. If the inflammation is because of residual CMV, it may be possible to minimize the risk of vitritis by continuing on CMV maintenance therapy for a longer period of time. For those people who do decide to stop CMV maintenance therapy, it is advisable to be routinely monitored by an eye specialist (ophthalmologist). One caveat to these results is that the study was conducted at the University of California, San Diego where they routinely use intraocular injections (injection directly into the eye) of cidofovir (Vistide^®) to treat people with CMV retinitis. This is not the approved route of administration for this drug. Additionally, there have been anecdotal reports of vitritis in people treated with intravenous (injections into the veins) cidofovir while on HAART.

Fungal Infections

A Thai study found that a combination of amphotericin B (Fungizone^®) and itraconazole (Sporanox^®) was significantly better at treating cryptococcal meningitis than amphotericin B alone. One hundred and thirty-three people with cryptococcal meningitis received amphotericin B (0.7 to 1mg/kg/day) or amphotericin B and itraconazole (200mg twice a day). Twenty-seven percent of the people receiving amphotericin B alone were considered treatment successes (two consecutive cultures from the cerebral spinal fluid which were clear of cryptococcal antigens) whereas 60% receiving the combination were considered treatment successes. Two important findings came out of this study. One is that this is potentially a highly effective combination regimen for people in the developing world with cryptococcal meningitis. Second is that it has long been argued that there is a potential antagonism between amphotericin B and the azole drugs (such as itraconazole and fluconazole). This study shows that this is clearly not the case, at least for treating cryptococcal meningitis.

AIDS-Related Diarrhea

Chronic diarrhea remains a problem for people with HIV disease. Diarrhea can be caused by HIV itself, by a parasite or by any number of different drugs commonly used by people with HIV. A recent study shows that a product (SP-303) derived from a plant found in the Central and South American rain forest may provide benefit for people with chronic diarrhea. The product blocks the amount of chloride that is produced in the gut and is therefore likely to be useful against many different forms of diarrhea. Fifty-one people with an average CD4+ count of about 225 cells, a viral load of about 8,000 copies HIV RNA and chronic diarrhea participated in the study. It appears likely that most study participants had diarrhea associated with the protease inhibitors or other medications. In only three people was the diarrhea known to be caused by a parasitic infection. Overall, volunteers had CD4+ cell counts and viral load levels associated with relatively low risk for parasitic infections. Participants received SP-303 (500mg every 6 hours) or placebo for 4 days, and the study required that all participants be admitted into the hospital for a five day stay so that they could be routinely monitored. Participants receiving the active drug had over 50% reduction in stool volume and also a reduction in stool frequency. SP-303 is thus likely to be a useful therapy for people with diarrhea. However as this drug might reduce the frequency of diarrhea, people should remember to also treat the underlying cause of the diarrhea.

Commentary

Although the overall incidence of opportunistic infections has decreased in developed countries since the introduction of the protease inhibitors, they remain a major issue for people who have had little or no benefit from them. Since developing nations have limited or no access to these new therapies, the overall incidence of opportunistic infections has not decreased in those countries. Furthermore, the most common opportunistic infections found in developing nations are often different than those in developed countries, the most common being esophageal candidiasis (a fungal infection in the esophagus), wasting disease and tuberculosis. One of the most urgent needs is to make sure that pharmaceutical companies continue to develop new therapies for opportunistic infections and to make sure that all medications are affordable and accessible in every country.

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The original of this article can be found at http://www.projinf.org/pub/25/oiupdate.html