HIV-Related Infections and Conditions

April 2008

This year at CROI, many studies covered a variety of topics related to HIV-related infections and conditions, such as tuberculosis, herpes and hepatitis. Some revealed modest advances, some exposed sobering news, while others provided us with a better understanding of how treating some infections impact HIV therapy. Some studies report possible advances in diagnostic tools that could better manage these infections and improve the lives of people living with HIV.

New Information on Abacavir Sensitivity

A serious condition called hypersensitivity reaction (HSR) can occur in 5-8% of people who take the HIV drug Ziagen (abacavir). [Abacavir is also found in the fixed-dose combination pills Epzicom (3TC + abacavir) and Trizivir (AZT + 3TC + abacavir).] Symptoms can appear within 2-6 weeks of taking it. They include fever, rash, headaches, upset stomach, tiredness, sore throat, cough and shortness of breath. They usually get worse over time and can be life-threatening, especially if a person stops and then restarts taking abacavir.

Finding a way to predict who would most likely develop abacavir HSR has the potential to greatly reduce the rate of this condition. Researchers found that people with the gene pair called HLA-B*5701 are more likely to develop abacavir HSR. The HLA test was developed several years ago to screen people before they started a regimen with abacavir. Two studies at CROI reported new information on abacavir HSR.

Study 1

The first study looked at using another gene associated with HLA to predict HSR, called HCP5-SNP. The research followed 108 people in the Swiss HIV Cohort Study who had stopped Ziagen due to possible HSR. A random sample of another 259 who already had HLA test results was also included. The study tested both HLA and HCP5 and then compared the results.

The study showed that all of those who carried HLA also carried NCP5. Only 1% of those who didn't carry HLA had NCP5. Therefore, using NCP5-SNP found everyone with HLA and was absent in 99% of those without HLA. Using NCP5 may lead the way to a simpler and cheaper screening test for people with HIV.

Study 2

Several studies have shown that HLA-B*5701 is greatly associated with abacavir HSR. However, people who could take abacavir safely have not been defined. The second study looked at trying to identify genes that would predict who could tolerate abacavir.

The research followed 95 volunteers with abacavir HSR from three studies, 40 of whom didn't have symptoms of HSR. The study measured the HLA gene and several gene markers related to abacavir metabolism in order to predict the likelihood of HSR. While one genetic variation was found to have a possible relationship to HSR, the authors concluded that the observed relationship wasn't strong enough to warrant more research.

Although HLA testing and perhaps now NCP5 testing are good markers for predicting abacavir HSR, they cannot predict every person who will develop the condition. People who start abacavir, even though they are negative for HLA or NCP5, should still be aware of any symptoms within the first six weeks of taking the drug and report them to their doctors as soon as possible. Put another way, genetic testing for HSR should augment, and not replace, clinical vigilance.

Bone Loss Increasingly an Issue for People Taking HIV Drugs

As people living with HIV take therapy over time, a growing list of conditions often become important, including bone problems. Research continues to examine the relationship between HIV and bone problems, including bone density loss (osteopenia), bone loss (osteoporosis), and bone death (osteonecrosis). Several studies reported findings at CROI 2008. Though they pointed to some general observations, they have not found the exact cause(s) for the higher rate of bone loss in people with HIV.

One study looked at two different regimens: Kaletra (lopinavir + ritonavir) or Sustiva (efavirenz) taken with Combivir (Retrovir/zidovudine + Epivir/lamivudine) for 24-48 weeks. People were then switched to Kaletra monotherapy through to 96 weeks. The results showed that loss of bone density occurred at about the same rate, suggesting that bone loss occurs independently of the HIV drugs used.

A second study seems to confirm these results. A sub-study of Hippocampe-ANRS 121 followed 71 people over 48 weeks and checked the bone density in the hip and spine. Three regimens that included three different classes of HIV drugs were used. The results showed that all three groups showed bone loss, suggesting again that HIV or HIV treatment contributes to the loss of bone density in people on HIV therapy.

Other studies showed the same types of risks for bone loss that HIV-negative people face, such as older age, low body mass, low activity level and poor nutrition. Risk factors unique to people with HIV include low CD4+ count, younger age than HIV-negative people, and low testosterone levels often found in HIV-positive men.

Nearly 2 in 3 people with HIV show signs of osteopenia. About 1 in 5 has osteoporosis. No standards of care have been established, such as how often to test for bone loss. So more study is necessary to find out the reasons for bone loss in people with HIV and whether and how they pose more of a health concern.

Changes in lifestyle and other strategies shown to prevent bone loss in postmenopausal women can also be used by people with HIV. This includes staying active and getting enough calcium and vitamin D in the diet or through supplements. Other lifestyle changes can also help including stopping smoking, drinking less alcohol and caffeine, and talking to a doctor about medicines that affect bone loss.

For more information on bone disease, read Project Inform's publication, Bone health and HIV disease.

Sobering Information on Genital Herpes and HIV

Several studies show that having genital herpes (herpes simplex virus-2, or HSV-2) increases the chance to get HIV by 2-3 times. HIV has a better chance of being passed when there's a genital ulcer present, and HSV-2 is the most common sexual infection that causes genital ulcers. A good deal of research has assessed the relationship of HIV and HSV-2. Several studies reported sobering information at CROI.

The HPTN 039 study followed over 3,000 people and looked at whether using oral acyclovir to control genital herpes would reduce the sexual transmission of HIV. At the start of the study, all tested negative for HIV and 26% of women and 12% of men tested positive for genital herpes. People took either 400mg acyclovir or placebo twice a day. Unfortunately, the results showed that taking acyclovir to control genital herpes did not lower the risk of HIV infection. A smaller study reported similar results last year.

A second study looked at how HIV and HSV-2 interact. Researchers infected human tissues with both viruses in the lab and examined their effects. HSV-2 easily replicated in the tissue while HIV helped in that process. HSV-2 also impaired the production of the cell protein, CCR5, which HIV uses to enter cells. Some think that R5 HIV is less aggressive than HIV that uses another protein, called CXCR4 (X4). These interactions may affect the course of a person's HIV disease.

Since living with both viruses is common in people with HIV, how they interact and to what degree they affect HIV disease is a great concern. These studies not only show how having HSV-2 can affect HIV prevention, they also show that having both viruses may affect the course of HIV disease. These results underscore the importance of people with HIV discussing all health issues with their health providers.

At the least these sobering results may lead to other research, including ones of higher doses of acyclovir, new drugs or combinations of them. At best, they may lead to developing an effective herpes vaccine.

For more information on herpes, read the publication, Oral and Genital Herpes.

HPV and Cervical Cancer

At CROI, two studies reported on the types of HPV found in HIV-positive and HIV-negative women in Africa. The first study followed 119 HIV-positive pregnant women and identified 27 distinct HPV types among 72 women. More half the women had high cancer risk types: HPV 58 and 66. Less than 1 in 5 women had the more common cancer risk types, 16 or 18.

In the second study, 200 women were tested for HPV and HIV. Nearly 2 in 3 women had HPV and 1 in 5 women had HIV. The most common high-risk HPV types found were 16, 53, 70 and 81. Women living with HIV were more likely to have other types of HPV, including both high- and low-risk types, than HIV-negative women. They also had a higher number and larger range of types. Not surprisingly, HIV-positive women were more likely to have an abnormal Pap smear.

What these study results show is that women living with HIV may be prone to a larger range of HPV types than HIV-negative women. Though current vaccines provide protection against some types of HPV, new vaccines may be needed to further protect women living with HIV.

What Is HPV?

Over 100 types of human papillomavirus (HPV) exist, and more than 40 can be easily passed through genital contact in men and women. Most do not cause symptoms or health problems, increasing a person's chance of passing it onto others. However, some cause genital warts while others cause cervical cancer. Though genital warts can change in shape and size, they do not turn into cancer.

Only one HPV vaccine called Gardasil is currently approved. It protects against two of the most common types that cause up to 70% of cervical cancer: HPV 16 and 18. It also protects against the two types that cause up to 90% of genital warts: HPV 6 and 11. The Gardasil vaccine is recommended for 11- to 12-year-old girls since nearly 3 in 4 new infections in the US occur in 15- to 24-year-old women. However, any woman is at risk throughout a sexually active life.

Another vaccine, Cervarix, is currently being studied in nearly 30,000 women worldwide. This vaccine protects against HPV 16, 18, 31 and 45, which are the four most common causes of cervical cancer.

HPV affects about 20 million men and women in the US. Aside from refraining from sex, the best way to help prevent HPV in women infection is by getting a vaccine, though it will not protect every woman who takes it. There's currently no HPV vaccine for men although it's now being studied.

HIV Drugs That Penetrate the CNS Help Control PML

PML, or progressive multifocal leukoencephalopathy, is a rare condition of the brain caused by the JC virus. Before the arrival of potent HIV therapy, a diagnosis of PML disease usually resulted in death within a few months. The one therapy used to treat it, a toxic drug called cytosine arabinoside, is given through a shunt directly into the brain and has shown marginal, if any, benefit. It is no longer routinely used, though some feel that new ways to deliver it should be researched.

As more HIV drugs have been developed during the HAART era, PML is diagnosed less often, and when it is diagnosed the survival rate has improved. This is due to using potent HIV therapy that reinforces a strong immune system which, in turn, keeps PML under control.

It is believed that an HIV protein called Tat helps create more JC virus in the central nervous system (CNS). At CROI, one study looked at which HIV drugs get into the CNS. The results showed that some HIV drugs control PML disease better than others due to their ability to get into the CNS.

HIV drugs with high penetration of the CNS are:

    Crixivan (indinavir) with or without Norvir
    Emtriva (emtricitibine, FTC)
    Kaletra (lopinavir + ritonavir)
    Rescriptor (delavirdine)
    Viramune (nevirapine)
    Retrovir (zidovudine, AZT)
    Ziagen (abacavir)

HIV drugs with moderate penetration are:

    Agenerase (amprenavir) + Norvir
    Epivir (lamivudine, 3TC)
    Lexiva (fosamprenavir) + Norvir
    Prezista (darunavir) + Norvir
    Reyataz (atazanavir) + Norvir
    Sustiva (efavirenz)
    Zerit (stavudine, d4T)

HIV drugs with low penetration are:

    Agenerase (amprenavir)
    Aptivus (tipranavir) + Norvir
    Fuzeon (enfuvirtide, T20)
    Hivid (zalcitabine, ddC)
    Invirase (saquinavir) with or without Norvir
    Norvir (ritonavir)
    Videx (didanosine, ddI)
    Viracept (nelfinavir)
    Viread (tenofovir)

What this means is that when faced with a diagnosis of PML, using HIV drugs that best penetrate the CNS leads to better survival for the individual. Building or switching to a regimen that includes these HIV drugs may go a long way to improving the health and life of the person faced with PML.

For more information on PML, read Project Inform's publication, PML.

Tuberculosis Update

Some people living with HIV encounter an undesirable condition called Immune Reconstitution Inflammatory Syndrome (IRIS) after starting therapy for the first time. A similar reaction can also result after starting HIV drugs as the immune system reacts to an already present infection, like tuberculosis (TB), as though it were new. When HIV therapy responds to TB in this way, the condition is called TB-IRIS. About one out of every three cases of IRIS is likely due to TB.

Neither IRIS nor TB-IRIS is well understood, and health providers lack clear definitions of them. This area of research is just now beginning to shed more light on what TB-IRIS means for people with HIV and their health providers. What is not well understood is who is more likely to experience TB-IRIS and what lab tests could be used to predict the condition, among others. Having these answers will better help diagnose, prevent and treat TB-IRIS in people with HIV.

One study presented at CROI examined several markers for their ability to predict who would and would not develop TB-IRIS: IL-12 and serum IL-2, among others. The results reported on 51 adults with TB in Thailand with average CD4 cell counts of 37 before starting HIV therapy. All were diagnosed with various types of TB disease: in the lungs (pulmonary), outside the lungs (extrapulmonary), and throughout the body (disseminated). After starting HIV therapy, 11 developed TB-IRIS within 14 days on average.

Unfortunately these studied markers did not show differences between the two groups, which could be used to better manage TB disease. Although this may sound like a failure, the results will help direct researchers to consider other markers for study. One such study is now looking at other markers, such as regulatory T cells, effector T cells and monocytes/macrophages. The hopeful outcome to this study is the same: to find ways to diagnose, predict and treat possible cases of TB-IRIS.

CROI also provided some update on new drugs in study for treating TB. For more complete coverage on drugs in the TB pipeline, read the article The Growing Renaissance in TB Drug Study.

For more information on TB disease, read Project Inform's publication, Tuberculosis and HIV Disease.

Hepatitis B Update

One study at CROI reported on results of how hepatitis B (HBV) affects HIV therapy over time. These areas included HIV levels, CD4 counts, and AIDS-related and non-AIDS-related death. Researchers used a MACS cohort and followed 822 men with HBV taking long-term HIV therapy. The results showed that HBV over time does not alter two markers of HIV therapy: CD4 counts or HIV levels. However, liver-related deaths were higher in those with chronic HBV and non-AIDS deaths were higher in those positive for HBcAb, a marker of HBV disease. These results are similar to what was reported from a South African study. After 72 weeks of HIV therapy in 539 people, no evidence was found that HBV affected the response to HIV treatment.

Two genotypes of HBV—A and D—are the most common ones found in people with HBV alone and HBV/HIV together. One study looked at how both affect use of Epivir (lamivudine, 3TC), a drug that's used to treat both HIV and HBV disease. The study followed 68 people with HBV who took Epivir an average of 41 months. The results showed that the type of HBV heavily influenced different mutations associated with resistance to Epivir. How this affects resistance to other HBV drugs is unknown.

Hepatitis C Update

Treating hepatitis C (HCV) disease in people living with HIV can be difficult. Currently, there's no standard of care for when to start HCV therapy in these individuals. It's generally believed, though, that treating HCV should be started when liver function is consistently abnormal. However, more recent data show that treating acute HCV infection early results in better outcomes. About 2 in 3 people who take effective HCV therapy maintain control of their acute HCV, while only about 1 in 3 with chronic HCV are able to control their disease. Several studies at CROI reinforce this, as well as provide other information on managing HCV and HIV disease.

In a very small study, researchers examined the effects of CD4 cells specific to HCV in HIV co-infection. Three people who were infected with both viruses at the same time were treated for both of them early in their co-infections and then followed and compared to a control group. Results showed that treating both infections early in the acute stage helped produce and maintain CD4 cells specific to the HCV infection, which in turn helped control their HCV disease.

A larger study of 150 HIV-positive men with acute HCV infection showed the same results. A total of 111 started HCV therapy: 14 with pegylated interferon and 97 with pegylated interferon + ribavirin. Treatment was started within 6 months of HCV infection and lasted from 23 to 43 weeks. Two out of three sustained control of their HCV infection and no differences were noted among the various types of HCV found in the study.

People living with chronic diseases like HCV and HIV have a higher risk for heart disease. The FRAM study looked at using a marker called C-reactive protein (CRP) to predict the risk of heart disease in people infected with both HIV and HCV. After analysis of 1,135 HIV-positive volunteers, HIV infection alone showed higher CRP levels in men but not in women. For co-infected people, lower CRP levels appeared in both men and women. These data raise the question whether CRP will predict heart disease differently in people with HIV and HIV/HCV. With more study, this marker may be developed to diagnose and help prevent heart disease. A similar result was found in a study of 19,424 co-infected veterans who had statistically significantly more heart attacks due to HCV disease.

The long-term benefits from using HCV therapy in people with chronic hepatitis C have been well established, including a lower risk of liver disease progression and death. However, these benefits in people with both HCV and HIV have not been studied. The GESIDA 3603 Study Group examined the long-term effects of using interferon + ribavirin to treat chronic HCV disease. The volunteers generally had good control of their HIV and all were treated with some form of interferon + ribavirin. Overall, 1 in 3 people sustained good control over their HCV, though that depended upon their type of HCV. Those with types 1 and 4 (14%) had less control of their HCV while those with types 2 and 3 (46%) had better control. Several studies have shown that types 1 and 4 are more difficult to treat.

A few observational studies have suggested that mothers with both HCV and HIV have a higher risk for passing HCV onto their children. In a Spanish study, 631 pregnant women were followed, of whom about 2 in 5 had both infections. Results showed that no cases of both HCV and HIV were passed, while seven transmission cases of HCV were reported. This rate is below what has been reported before.

An Italian study examined the rate of AIDS-defining malignancies in 6,285 HIV-positive people with HBV or HCV infection. The malignancies studied were non-Hodgkin lymphomas and cervical cancer. Of the total volunteers, 38% had HCV and 5% had HBV. The results showed that those living with HIV and HBV or HCV had a higher risk for an AIDS-defining malignancy, especially if cirrhosis had been diagnosed. However, these same individuals were not at higher risk for other AIDS-defining illnesses like herpes or TB.

Hepatitis D

In general, hepatitis is a major concern for people living with HIV. Many live with chronic HBV and/or HCV infection, which can worsen liver health and challenge treatment regimens. Another hepatitis virus, hepatitis D (HDV), can further complicate matters when it's present with HBV or even HBV/HCV.

HDV must use parts of HBV to live and reproduce, specifically the hepatitis B surface antigen, HBsAg. One study reported on using HBsAg as a way to better manage HDV disease. A small study followed 16 people with chronic HDV after starting HIV therapy with either Epivir (lamivudine, 3TC), Viread (tenofovir) or Emtriva (emtricitibine). A significant relation was found between the levels of HDV and HBsAg. Ten of the volunteers showed a decrease between the two levels at the same time. For the other six, no significant change was found despite successfully treating HBV. The study concluded that checking HBsAg levels may be useful in managing HDV disease in some people.

For more information on hepatitis D, read Project Inform's publication, Hepatitis D.

This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.


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