Opportunistic illness and viral hepatitis co-infection
Dr Mark Nelson for HIV i-Base
The advent of antiretroviral therapy has clearly revolutionised the lives of those living with HIV disease. The successful use of HAART has led to a decline in incidence of opportunistic infections and tumours, and allowed many individuals who were staring at a severely shortened life span to lead lives of not only increased quantity, but also quality. Sullivan  presented data from CDC Atlanta showing a decline in opportunistic infections.
From 1993 – 1998 there was a statistically significant decline in opportunistic infection in all evaluated groups, although from 1996 – 1998 there was only a significant decline in homosexual and intravenous drug using men. However, data from the University of California, presented by Jacobson  showed clearly that patients continue to die of AIDS related conditions, and by no means is the war against HIV over. In this study the strongest predictor of death remained a low CD4 count. Therefore although we strive for the “holy grail” of the undetectable viral load, it is important to realise that CD4 count remains the prime indicator for possibility of opportunistic infection.
In patients who do have a CD4 count response, there is now a significant amount of data that shows both primary and secondary prophylaxis against opportunistic infection may be stopped. In yet another presentation of the GESIDA study, the stopping of both primary and secondary toxoplasmosis prophylaxis has been shown to be safe. There has however been only limited data on stopping cryptococcal prophylaxis, previous data on small numbers presented by Nwokolo at BHIVA and by Alberg at the San Francisco Retrovirus Conference, has suggested that it may be safe to stop secondary prophylaxis against this condition.
Mussini et al add to this database  by presenting data on 24 individuals with cryptococcal meningitis. Mean CD4 count at the time of diagnosis was 42, and after a meantime of HAART of 22 months, the mean CD4 count has increased to 251 cells, though 6 patients had a CD4 count below 100. Cryptococcal neoformans meant that prophylaxis was stopped in 14 patients. Ten of whom had a serum cryptococcal antigen which was negative. After a mean time of follow up of 27 months there were no case of relapse of meningitis. There were similarly no cases in those who continued. As 6 patients had a CD4 count of below 100, but still had no evidence of cryptococcal neoformans disease relapse, the authors suggested that their HAART regime, which in all cases contained a protease inhibitor, may have had a direct anti cryptococcus effect. There is no data however to back this suggestion up in vitro. Although there is increasing amount of data on stopping cryptococcal meningitis prophylaxis, some patients may still be wary of doing so.
Many individuals affecting with HIV also have other sexually transmitted diseases. Perhaps the most common of these is infection with the human papilloma virus which has been linked to the development of cervical and anal neoplasia. In an important study by Luke  women who received antiretroviral therapy had a lower incidence of abnormalities on cervical smear than those women who did not receive highly active antiretroviral therapy, suggesting that immune reconstitution may be an important factor in reducing the incidence of these tumours.
Progressive multifocal leucoencephalopathy (PML) continues to occur in individuals. Although previously mostly described in those with low CD4 counts who had failed antiretroviral therapy, in our clinic we have seen patients who have developed PML despite reconstitution. Diagnosis of PML is made on typical MRI findings, and confirmed on testing of cerebral spinal fluid, for the causative agent the JC virus. Data from Diaz  suggests that quantitative measurement of JC did not give important information on extension of CNS lesions, or survival, suggesting that this test is no more useful than the standard qualitative testing.
In some areas of the world, infection with hepatitis B and hepatitis C is now one of the leading causes of morbidity and mortality for those living with HIV. Hepatitis B infection was shown to occur in a rate of approximately 40 times higher in those who are HIV positive, compared with a HIV negative controlled population.  They suggest that 3TC should be included in antiretroviral therapy regimens, in areas of high chronic hepatitis B virus infection. Although approximately 30% of patients at 3 years may seroconvert who receive 3TC as mono therapy, it remains unclear whether such a high level will be reached in those who are HIV positive.
Previous authors have reported that single agent use of 3TC may rapidly lead to the development of HBV 3TC resistance, and although there are reports of continuing sero conversions in patients with 3TC resistance, it would appear better that we learn our lessons from HIV disease and await the development of newer agents for the treatment of this condition, and then to give dual or triple therapy. There have been recent reports of a small number of patients responding to dual therapy with 3TC and famciclovir, although this approach awaits further confirmation.
There was some good news for those infected with hepatitis B, with reports of entacovir in the Woodchuck  and some early studies of emtricitabine  showing potential activity against this virus.
HIV-positive intravenous drug users are commonly co-infected with hepatitis C, and also homosexual men with HIV may have an incidence of over 10% of co-infection with this agent. It is well know that with hepatitis C individuals may have normal liver function tests, despite ongoing inflammation and development of fibrosis. Hoffman-Terry et al presented data on 10 patients with normal liver function tests who underwent biopsy .
8 of these patients, on whom many physicians may have felt biopsy inappropriate, showed substantial inflammation and fibrosis. It is therefore important that all HIV-positive patients are tested for co-infection with hepatitis C and that even those individuals with normal liver functions tests should consider undergoing biopsy. The aim of biopsy would be to try and choose which individuals may require and benefit from treatment. There has been some concerns over the treatment of hepatitis C with interferon (which may have many toxic side-effects), and ribavirin (which may have interactions with agents used in HAART). However the development of pegylated interferon which is interferon wrapped in polyethylene glycol, may reduced the toxicity and increase the efficacy of this agent. Studies are underway at several centres in London of this agent in co-infected patients, and physicians are encouraged to refer these patients for assessment to those centres of care.
- Sullivan PS et al. Trends in AIDS-defining opportunistic illness diagnoses through 1998. Abstract I-1906. 40th ICAAC, Toronto, Canada, Sep 2000.
- Jacobson S et al. Causes and predictors of death among people with HIV in the era of highly active antiretroviral therapy (HAART). Abstract I-1907. 40th ICAAC, Toronto, Canada, Sep 2000.
- Mussini C et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in AIDS patients receiving HAART. Abstract I-1912. 40th ICAAC, Toronto, Canada, Sep 2000.
- Luque AE et al. Effect of highly active antiretroviral therapy (HAART) on human papillomavirus (HPV) infection and disease among HIV-infected women. Abstract H-66. 40th ICAAC, Toronto, Canada, Sep 2000.
- Diaz MS et al. Progressive multifocal leukoencephalopathy (PML): Is measurement of JCV load in CSF worthwhile? Abstract H-71. 40th ICAAC, Toronto, Canada, Sep 2000.
- Kellerman SE et al. Incidence of chronic hepatitis B infection in HIV infected individuals and the protective effect of lamivudine; data from the adult/adolescent spectrum of HIV disease (ASD) project. Abstract H-1406. 40th ICAAC, Toronto, Canada, Sep 2000.
- Colonno RJ et al. Long-term therapy with entecavir (BMS-200475) in the woodchuck model of chronic hepatitis infection. Abstract H-172. 40th ICAAC, Toronto, Canada, Sep 2000.
- Robertson AT et al. Antiviral activity of emtricitabine in a phase I/II dose escalation trial, FTCB-101. Abstract H-1407. 40th ICAAC, Toronto, Canada, Sep 2000.
- Hoffman-Terry M et al. Correlation of ALT with degree of liver damage by biopsy in HIV/HCV coinfected adults. Abstract H-175. 40th ICAAC, Toronto, Canada, Sep 2000.