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Project Inform - April, 1998
Although the improved immune response associated with HAART has been shown to delay progression and relapse of various HIV-related infections, it may not control infections that have already started, and are just beginning to establish themselves, at the time that HAART is initiated. While the use of HAART has dramatically decreased the overall incidence of OIs, HAART doesn’t work for everyone, for a variety of reasons. Thus, it has not eliminated all OIs nor has it eliminated the need for preventative or maintenance therapies in all cases. More research is clearly needed to determine the appropriate use of preventative and maintenance medications in this new era of anti-HIV treatment.
A study recently provided insight into something being termed "MAC reversal syndrome." The study showed that individuals who already have MAC when initiating HAART sometimes have an unusual inflammatory response due to increased immune function. This syndrome involves fevers and the growth of a mass or masses usually around the neck or spine. The addition of prednisone appeared to lessen the inflammatory reaction. Over time, these individuals still benefited from HAART with dramatic decreases in HIV levels and increases in CD4+ cell counts and their MAC infection stabilized. Thus, HAART does not necessarily prevent MAC in persons fostering infection, but ultimately seems to be beneficial whether or not MAC occurs. While this study is small, it suggests that people who have active manifestations of MAC, such as fevers and other symptoms, should remain on HAART and anti-MAC therapies during such an episode.
A recent multinational study of 1583 people who were both HIV-positive and PPD-positive (positive for TB) found that 2 months of rifampin (600 mg once a day) + pyrazinamide (20 mg/kg once a day) was just as effective at preventing active TB as 12 months of isoniazid (INH) (300 mg once a day). INH has long been considered the gold standard for preventing TB. There was no difference in the magnitude of side effects between the two regimens. As expected, adherence in the 2 month regimen was significantly better, with 80% of people completing the 2 month regimen compared to less than half completing the INH regimen. This shorter course of therapy is particularly interesting because HIV infection is known to hasten the progression of TB disease as well as increase the rate of activation of latent TB infection. Furthermore, some studies have found that TB can further stimulate HIV replication. Therefore, a shorter course of therapy which might improve adherence would be particularly beneficial for people who are co-infected with HIV and TB. Additionally, this short-course regimen is likely to be less expensive than a year of INH–perhaps allowing countries which currently cannot afford the use of INH to start TB prevention campaigns. The rifampin + pyrazinamide combination provides a safe and effective regimen for the prevention of TB, however, there are significant potential drug interactions associated with the use of rifampin which may impact a person’s decision to opt for this regimen.
Several studies looking at PCP preventative regimens in the era of HAART still show occasional breakthrough cases of PCP. All studies confirm the use of TMP/SMX (Bactrim or Septra) as the first line preventative therapy. For those who are intolerant to TMP/SMX, data from two studies covering a total of 1057 people compared dapsone (100 mg once a day) and atovaquone suspension (Mepron) (1500 mg once a day) for the prevention of PCP. Results from the combined studies showed the two therapies to be equally effective. Additionally, there was no difference in the incidence of toxoplasmosis between the two groups. This was somewhat of a surprise since dapsone has been the drug of choice for those who can not tolerate TMP/SMX. Additionally, there has been concerns that the original version of atovaquone was not absorbed well into the bloodstream resulting in insufficient blood levels of drug to prevent PCP. The new studies used an improved formulation of atovaquone. People receiving dapsone were more likely to develop rash and anemia (a decrease in red blood cells) while people receiving atovaquone were more likely to experience gastrointestinal side effects. In this large study, people receiving atovaquone had fewer drug discontinuances than people receiving dapsone, suggesting that atovaquone may be preferable to dapsone for people who cannot tolerate the standard therapy (TMP/SMX).
A second study also confirms atovaquone as a useful second line therapy for PCP prevention for people who can not tolerate standard therapy (TMP/SMX). Four hundred and seventy-six people received aerosolized pentamidine (Nebupent) (300 mg monthly) or one of two doses of atovaquone suspension (either 1500 mg or 750 mg once a day). There were no differences in the number of PCP cases between the three groups. People receiving either dose of atovaquone were significantly more likely to develop rash while people receiving aerosolized pentamidine were more likely to develop bronchospasms.
As with all other OIs, the rates of candidiasis or thrush have decreased. Several studies have looked at the role of maintenance therapy (to prevent the recurrence of thrush) for people who have a history of recurrent thrush but are responding well to HAART. One study found that withdrawal of azole-suppressive therapy, such as fluconazole (Diflucan) and itraconazole (Sporanox), for maintenance of recurrent thrush in people responding to HAART did not result in significant relapse. Only two of twenty people had any recurrence of candidiasis after withdrawal of maintenance therapy. In both cases, it was a single episode controlled with a short course of fluconazole and there was no further recurrence during the median 5 months of follow-up. This would suggest that for those people experiencing immunologic and virologic responses to HAART, need for maintenance therapy may lessen over time, as the immune system recovers.
For people with candidiasis not responsive to standard therapy, a small study found that 3 people resolved their disease with the use of GM-CSF (Leukine, 300 micrograms/subcutaneous (under the skin for 14 days) as an adjunctive therapy to fluconazole (400 mg/once a day). While the numbers here, again, are quite small, further investigation into the use of GM-CSF in this setting is warranted.
Nitazoxanide (NTZ) is an anti-parasite compound recently submitted to the Food and Drug Administration for consideration for approval for its antidiarrheal activity. In studies, NTZ has been shown to decrease stool frequency by at least 50% in about 40% of people who have thus far received the drug. About 20% of people have had a complete response with no cryptosporium eggs (oocysts) detectable. NTZ is dosed at 500 mg twice a day and escalated to 1000 mg twice a day if no response is seen in a minimum of 4 weeks. This is the first evidence of a single drug having activity against cryptosporidiosis. It is likely that NTZ in combination with other antiparasitic drugs may have even better activity against cryptosporidiosis.
A recent study showed that paromomycin (Humatin) (1 gram twice a day) and azithromycin (Zithromax) (600 mg once a day), used in combination, may also be an effective treatment for cryptosporidiosis. This is important as neither drug alone has shown efficacy against this organism. In this study, volunteers experienced marked reductions in oocysts, 40% reduction in the number of stools per day and a reduction in overall stool volume per day.
In the search for new classes of drugs, fomivirsen (formerly known as ISIS 2922), an antisense drug against CMV, was studied in 28 people with newly diagnosed CMV retinitis. People received either immediate or deferred therapy. Participants were given 150 µg by direct injection into the eye once weekly for three weeks, and then put on maintenance therapy at 150 µg once every other week. The deferred therapy group had progression of their CMV retinitis in a median time of 13 days compared to 71 days for the immediate treatment group. The most common side effects were increased pressure in the eye. This study shows that fomivirsen may be a useful drug for the treatment of CMV retinitis. Additionally, laboratory studies show that fomivirsen is active against CMV which is resistant to other commonly used anti-CMV therapies such as ganciclovir (Cytovene), foscarnet (Foscavir) and cidofovir (Vistide). However, these results do not compare favorably with those seen from some other treatments for CMV, most notably the ganciclovir implants, which offer a much longer "time to relapse" than that cited here. Other new drugs under study for CMV include valgan-ciclovir, a new and much more potent form of oral ganciclovir. All studies of new drugs for CMV remain hampered by slow recruitment rates caused by the success of HAART in preventing new incidences of CMV.
At last year’s conference there were several anecdotal reports of resolution of Kaposi’s Sarcoma (KS) occurring concurrent to viral load decreases observed as a result of highly active anti-HIV regimens that included a protease inhibitor. This year a French group reported on 13 people with KS, 8 had cutaneous KS (skin lesions) and 5 had pulmonary (in the lung) KS. Participants were followed for 1 year after initiating a highly active protease inhibitor containing regimen. Study participants were also allowed to employ conventional chemotherapy for treating KS in concert with a 3-drug regimen. Among those with pulmonary KS, 3 of 5 experienced a complete response (i.e. resolution of KS) and 4 of the 5 are still alive 15 months after the initiation of the study. This type of response, particularly among people with pulmonary KS, has not been previously observed with chemotherapy alone. Among those with cutaneous KS, 4 of 8 experienced a complete response. Remission of KS, in this study, is also associated with a decrease in levels of HHV-8 (also known as KSHV), a herpes family virus believed to be associated with Kaposi’s Sarcoma.
Another study showed a correlation with increases in viral levels and KS disease progression. A Chicago group presented information on 27 people with KS, identified between January 1996 and October 1997. In this group, rises in HIV RNA levels (greater than ½ log increase) proceeded KS disease progression. Of the 18 individuals who experienced a greater than ½ log increase in HIV RNA levels, all experienced KS disease progression within 2 months. The other 9 individuals observed had stable HIV RNA levels and only 2 of these individuals experienced KS disease progression within the study period. This would suggest that persons with KS who experience rises in viral levels should consider more frequent monitoring of viral load (e.g. repeat test within a few weeks) and consider making changes in their anti-HIV regimens. The flip side of this coin, in this study, is that KS improvements following decreases in HIV RNA levels were much more variable.
Several of the studies described above suggest that we are entering a new era in the treatment and prevention of opportunistic infections. Although the data are not yet complete, it is becoming clear that when HAART is successful, it has a major impact on the occurrence of new opportunistic infections and on the need for continued maintenance therapy for those who had such infections previously. Under the best of circumstances, it appears that HAART results in a strengthened immune response which is sufficiently potent to allow discontinuation of OI maintenance therapies. Similarly, when HAART is effective, it sometimes eliminates the need for the preventative therapies previously employed at certain set CD4+ levels. However, how this applies to individuals is not at all clear. Studies have not yet provided enough information to predict who can and cannot safely forego preventative or maintenance therapies. In theory, there may someday be a measure of the strength of immune response which would make it easy to know who can and cannot forego these therapies. For now, it seems largely a matter of guess work, and thus, a decision which comes with considerable risk.
While we lack precise knowledge on how to make decisions about OI prevention and maintenance today, we do know a few things which might help guide such decisions:
Over time, better measures of immune response, including perhaps tests which might predict an individuals capacity to response to specific OIs might become routinely available. Until such time, the issue of OI preventative and maintenance therapy will be a highly individualistic matter, one which must be decided very carefully by each individual and his or her physician. In extreme examples – people with the best and worst responses to HAART – the decisions are relatively easy to make. For those who fall between, however, it remains a subject which must be addressed with great care. Each significant OI, if and when it comes or recurs, has the potential to do serious and lasting harm, as well as to derail otherwise stable treatment with HAART.
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