Barriers to HIV testing in older children

Concerns about guardianship and privacy can discourage clinics from testing children for HIV, according to new research from Zimbabwe. The results of the study, by Rashida A. Ferrand of the London School of Hygiene & Tropical Medicine and colleagues, provide much-needed information on how to improve care of this vulnerable population.

More than three million children globally are living with HIV (90% in sub-Saharan Africa) and in 2011 an estimated 1000 infant infections occurred every day. HIV acquired through mother-to-child transmission around the time of birth is often unsuspected in older children, and the benefits of treatment are diminished in children who develop symptoms of immune system failure before infection is discovered.

Provider-initiated HIV testing and counseling (PITC) involves health care providers routinely recommending HIV testing and counseling when people attend health care facilities. To investigate the provision and uptake of PITC among children between 6 and 15 years old, the researchers collected and analyzed data from staff at 6 clinics in Harare, Zimbabwe.
Among 2,831 eligible children, about three-quarters were offered PITC, of whom 1,534 (54.2%) consented to HIV testing. The researchers diagnosed HIV infection in about 1 in 20 (5.3%) of the children tested, highlighting the need for more effective PITC. HIV infection was also found in 1 out of 5 guardians who tested with a child.

The main reasons that health-care workers gave for not offering PITC were perceived unsuitability of the accompanying guardian to provide consent for HIV testing on behalf of the child, and lack of availability of staff or HIV testing kits. Children who were asymptomatic, older, or attending with a male or a younger guardian were less likely to be offered HIV testing. Male guardians were less likely to consent to their child being tested.

In interviews, health-care workers raised concerns that a child might experience maltreatment if he or she tested positive, and showed uncertainty around whether testing of the guardian was mandatory and whether only a parent (if one was living) could legally provide consent. When parents were alive but not present, seeking consent from another adult raised ethical concerns that a positive HIV test in a child would disclose the HIV status of a parent who hadn't provided consent.

The study, which was funded by the Wellcome Trust, did not explore the reasons for refusal of HIV testing by clients. Also, because the relationship of the child to the accompanying adult was not available, the appropriateness of the guardian could not be independently ascertained.

Lead author Dr. Rashida Ferrand from the London School of Hygiene & Tropical Medicine said: "The fear of the stigma faced by the child and their family seems to be discouraging caregivers from testing children for HIV. However, with improved clarity of guidelines, engagement with staff, and organisational adjustments within clinics, it should be possible to harness the commitment of health-care workers and properly implement HIV testing and counseling."

In an accompanying Perspective, Mary-Ann Davies and Emma Kalk of the University of Cape Town, who were uninvolved in the study, point out that "The fact that >90% of infected children had a previous missed opportunity for testing indicates suboptimal pediatric PITC coverage in most routine settings," and call for "clear HIV testing policies for children and guidance on guardianship, together with training of [health-care workers] on such policies."

Men living with HIV have a lower risk of prostate cancer

Incidence of prostate cancer is significantly lower among men living with HIV, investigators from California report.

“We found a 27% reduced risk of prostate cancer among HIV-positive men after adjustment,” comment the authors. “HIV-positive men were more likely to be tested and were diagnosed with lower-stage cancers and lower PSA [prostate specific antigen].”

Thanks to antiretroviral therapy, an ever-increasing proportion of people with HIV are now living into older age. The diseases of ageing are therefore an increasingly important cause of illness among people living with HIV. For instance, diagnoses of prostate cancer increased fivefold among men living with HIV in the US between 1991 and 2005. Despite this, infection with HIV has been associated with a 20 to 25% reduction in the risk of being diagnosed with prostate cancer. It has been suggested that this is due to lower screening rates.

Investigators from Kaiser Permanente in California wanted to see if infection with HIV really was associated with a reduced risk of being diagnosed with prostate cancer and if this could be attributed to lower levels of PSA screening.

They therefore designed a case-controlled study matching each HIV-positive participant with ten HIV-negative controls who entered care in the same year, were of a similar age and were receiving care at the same centre.

Incidence of prostate cancer was compared between the HIV-positive and HIV-negative men, adjusting for potential confounders such as age, race, smoking, drug or alcohol use, diabetes and testosterone levels.

Data were also collected on rates of PSA screening for men enrolled in Northern California.

Study participants entered care after 1996 (Southern California) or 2000 (Northern California). The study population included 17,424 HIV-positive and 182,799 HIV-negative men. They were followed for a mean of 4.2 and 5.0 person-years/subjects, respectively. The groups were of similar age. However, the men living with HIV were more likely than the HIV-negative men to be white and to report a history of smoking (39 vs 23%), alcohol abuse (12 vs 7%), drug abuse (15 vs 4%) and testosterone deficiency (13 vs 1%). Prevalence of diabetes and obesity did not differ by HIV status.

Almost two-thirds of HIV-positive men (62%) were in the men who have sex with men (MSM) risk group. Only 42% of the men living with HIV were taking antiretroviral therapy at the time they entered the study. By the end of follow-up, 76% were taking HIV treatment, mean CD4 count was 466 cells/mm3 and 61% had a viral load below 500 copies/ml.

Prostate cancer was diagnosed in 74 HIV-positive and 1195 HIV-negative men. Differences according to HIV status were observed. Men living with HIV were more likely to be diagnosed with less advanced cancers (state II, 95 vs 89%; stage III-IV, 5 vs 11%) and to have localised (93 vs 83%) rather than regional/distal (3 vs 14%) cancers. Recent PSA levels were lower among men living with HIV (10 vs 17).

Overall incidence of prostate cancer was 102/100,000 person-years for men living with HIV compared to 131 per 100,000 person-years for HIV-negative men. After controlling for potential confounders, men living with HIV had a 27% reduction in the risk of prostate cancer (RR = 0.73; 95% CI, 0.57-0.92). The association between HIV infection and a reduced risk of prostate cancer was strongest for more advanced cancers (stage III/IV, RR = 0.28; 95% CI, 0.009-0.90; regional/distal cancers, RR = 0.28; 95% CI, 0.11-0.68). However, men living with HIV also had a reduced risk of less severe forms of cancer (stage II, RR = 0.77; 95% CI, 0.60-1.01; localised cancers, RR = 0.81; 95% CI, 0.63-1.05).

These differences could not be explained by lower levels of screening among men living with HIV. In fact, a higher proportion of HIV-positive than HIV-negative men had undergone PSA screening by the age of 55 (91 vs 86%, p < 0.001).

The investigators restricted their analysis to the sub-set of men in Northern California who had PSA testing. After adjustment, men living with HIV had a significantly reduced risk of prostate cancer (RR = 0.55; 95% CI, 0.39-0.80).

“Our results suggest that the observed lower incidence of prostate caner among HIV-positive men…is attributable to factors other than differences in PSA screening,” comment the investigators.

No HIV-related characteristics were associated with prostate cancer risk. For both HIV-positive and HIV-negative men, risk of the cancer increased with age (p < 0.001) and was also associated with black vs white ethnicity.

The investigators call for further research to investigate why men living with HIV have a lower risk of prostate cancer.

Soy sauce molecule may unlock drug therapy for HIV patients

For HIV patients being treated with anti-AIDS medications, resistance to drug therapy regimens is commonplace. Often, patients develop resistance to first-line drug therapies, and are forced to adopt more potent medications. Virologists at the University of Missouri now are testing the next generation of medications that stop HIV from spreading, and are using a molecule related to flavor enhancers found in soy sauce, to develop compounds that are more potent than other.

"Patients who are treated for HIV infections eventually develop resistance to the drugs that prevent an effective or successful defense against the virus," said Stefan Sarafianos, associate professor of molecular microbiology and immunology in the University of Missouri School of Medicine, and a virologist at the Bond Life Sciences Center at MU. "EFdA, the molecule we are studying, is less likely to cause resistance in HIV patients because it is more readily activated and is less quickly broken down by the body as similar existing drugs."

In 2001, a Japanese soy sauce company inadvertently discovered the EFdA molecule while trying to enhance the flavor of their product. The flavor enhancer is part of the family of compounds called "nucleoside analogues" which is very similar to existing drugs for the treatment of HIV and other viruses. EFdA samples were sent for further testing, which confirmed EFdA's potential usefulness against HIV and started more than a decade of research.

EFdA, along with eight existing HIV drugs, is part of the class of compounds called nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs "hijack" the HIV replicating process by "tricking" building blocks inside the virus. Since EFdA appears similar to those building blocks, the virus is misled into using the imposter, which prevents HIV replication and halts the spread of the virus.

In their latest study, Sarafianos and his colleagues, including researchers from the University of Pittsburgh and the National Institutes of Health, helped define how EFdA works on a molecular level. Using virology techniques and nuclear magnetic resonance spectroscopy (NMR), they pieced together the exact structure and configuration of the molecule. Compounds developed by Sarafianos and his team currently are being tested for usefulness as potential HIV-halting drugs with pharmaceutical company Merck.

HIV-positive women respond well to HPV vaccine

HIV-positive women respond well to a vaccine against the human papillomavirus (HPV), even when their immune system is struggling, according to newly published results of an international clinical trial. The study's findings counter doubts about whether the vaccine would be helpful, said the Brown University medical professor who led the study. Instead, the data support the World Health Organization's recommendation to vaccinate women with HIV.

HPV causes cervical and other cancers. The commonly used HPV vaccine  had not been tested in seriously immune-suppressed women with HIV, said Dr. Erna Milunka Kojic, associate professor of medicine at the Warren Alpert Medical School of Brown University and The Miriam Hospital. Despite the WHO recommendation, she said, skeptics have wondered whether the vaccine would be safe and helpful for women with weakened immune systems who were already likely to have been exposed to HPV through sex. Vaccines are often less effective in HIV-positive people.

To address that debate, Kojic's study, dubbed "AIDS Clinical Trials Group Protocol 5240," measured the safety and immune system response of the vaccine in HIV-positive women aged 13 to 45 with a wide range of immune statuses. In the vast majority of the 315 volunteers who were vaccinated at sites in the United States, Brazil, and South Africa, the vaccine built up antibodies against HPV and posed no unusual safety issues during the 28 weeks they were each involved.

"The vaccine works for HIV-infected women in terms of developing antibodies," Kojic said.

Co-author Dr. Susan Cu-Uvin, professor of public health and of obstetrics and gynecology at Brown, said women with HIV are especially susceptible to cervical cancer from HPV because their weakened immune systems are less able to clear the virus. That makes vaccinating HIV-positive women especially important, so long as it's safe and they respond.

"This is a very safe vaccine. It doesn't have any systemic side effects among these women who are already taking medicine for other conditions."

Response across the board

To investigate that response in the context of HIV, the study grouped women by their CD4 cell count, a measure of immune system health. Group A had CD4 counts above 350, group B rested between 200 and 350. Group C was composed of women with counts below 200, the defining level of AIDS for which response to an HPV vaccine had not yet been studied.

 "Quadrivalent" vaccine, in that it protects against four types of HPV (6, 11, 16, and 18). Each group in the study, therefore, had four measures of "seroconversion," or the buildup of a significant army of antibodies against each type of HPV. The researchers determined that seroconversion in at least 70 percent of patients for each HPV type would define success.

"Seroconversion proportions at week 28 among women in CD4 stratum A were 96 percent, 98 percent, 99 percent, and 91 percent for HPV types 6, 11, 16, and 18 respectively; in stratum B, 100 percent, 98 percent, 98 percent, and 85 percent; and in stratum C, 84 percent, 92 percent, 93 percent and 75 percent for each type respectively," the authors wrote.
Seroconversion rates were clearly lower for women with the weakest immune systems, but still high enough to be worthwhile, Kojic said. And although some of the women in the study had already been exposed to at least one type of HPV, only 1 in 25 had been exposed to all four, suggesting that even older, sexually active women can benefit from vaccination.

The extent of the benefit, she acknowledged, is not yet clear because the trial did not measure the vaccine's efficacy in preventing cancers. It only measured safety and the number of patients who had the desired immune system response. But that response has been shown to be effective in other studies of other populations of women.

What is clear from the study is that the vaccine produced no more side effects or problems than any vaccine typically does.

"Comparing vaccine reactions, this is a very safe vaccine," Kojic said. "It doesn't have any systemic side effects among these women who are already taking medicine for other conditions."

Kojic said she hopes that by confirming that women with HIV are responsive to the vaccine without unusual adverse effects, more doctors will vaccinate HIV-positive patients.

Low cholesterol in immune cells tied to slow progression of HIV

People infected with HIV whose immune cells have low cholesterol levels experience much slower disease progression, even without medication, according to University of Pittsburgh Graduate School of Public Health research that could lead to new strategies to control infection.

The Pitt Public Health researchers found that low cholesterol in certain cells, which is likely an inherited trait, affects the ability of the body to transmit the virus to other cells. The discovery, funded by the National Institutes of Health (NIH).

When HIV enters the body, it is typically picked up by immune system cells called dendritic cells, which recognize foreign agents and transport the virus to lymph nodes where it is passed to other immune system cells, including T cells. HIV then uses T cells as its main site of replication. It is through this mechanism that levels of HIV increase and overwhelm the immune system, leading to AIDS. Once a person develops AIDS, the body can no longer fight infections and cancers. Prior to effective drug therapy, the person died within one to two years after the AIDS diagnosis.

"We've known for two decades that some people don't have the dramatic loss in their T cells and progression to AIDS that you'd expect without drug therapy," said lead author Giovanna Rappocciolo, Ph.D., an assistant professor at Pitt Public Health. "Instead the disease is much slower to progress, and we believe low cholesterol in dendritic cells may be a reason."

The discovery was made possible by using 30 years of data and biologic specimens collected through the Pitt Men's Study, a confidential research study of the natural history of HIV/AIDS, part of the national NIH-funded Multicenter AIDS Cohort Study (MACS).

"We couldn't have made this discovery without the MACS. Results like ours are the real pay-off of the past three decades of meticulous data and specimen collection," said senior author Charles Rinaldo, Ph.D., chairman of Pitt Public Health's Department of Infectious Diseases and Microbiology, and professor of pathology. "It is thanks to our dedicated volunteer participants that we are making such important advances in understanding HIV, and applying it to preventing and treating AIDS."

Medications called combination antiretroviral therapy (ART) disrupt the viral replication process and can delay the onset of AIDS by decades.

However, even without taking ART, a small percentage of people infected with HIV do not have the persistent loss of T cells and increase in levels of HIV after initial infection. They can sometimes go many years, even more than a decade, without the virus seriously compromising the immune system or leading to AIDS.

Through the Pitt Men's Study/MACS, eight such "nonprogressors" were assessed twice a year for an average of 11 years and compared to eight typically progressing HIV-positive counterparts.

Dr. Rappocciolo and her colleagues found that in nonprogressors, the dendritic cells were not transferring the virus to T cells at detectible levels. When taking a closer look at these dendritic cells, the researchers discovered that the cells had low levels of cholesterol, even though the nonprogressors had regular levels of cholesterol in their blood. A similar finding was shown for B lymphocytes, which also pass HIV to T cells, leading to high rates of HIV replication.

Cholesterol is an essential component of the outer membranes of cells. It is required for HIV to replicate efficiently in different types of cells. None of the study participants were taking statins, which are cholesterol-lowering medications that some people take to prevent vascular problems when cholesterol in their blood is too high.

When HIV was directly mixed with the nonprogressors' T cells in the laboratory, those T cells became infected with the virus at the same rate as the T cells of the regularly progressing, HIV-positive participants. Indeed, T cells from the nonprogressors had normal levels of cholesterol.

"This means that the disruption is unlikely to be due to a problem with the T cells, further supporting our conclusion that the slow progression is linked to low cholesterol in the dendritic cells and B cells," said Dr. Rappocciolo.

"What is most intriguing is that dendritic cells in the nonprogressors had this protective trait years before they became infected with HIV," Dr. Rinaldo said. "This strongly suggests that the inability of their dendritic cells and B cells to pass HIV to their T cells is a protective trait genetically inherited by a small percentage of people. Understanding how this works could be an important clue in developing new approaches to prevent progression of HIV infection."