CTN 277: CARMA endo study

About The Study

The purpose of this observational study was to assess the prevalence of various endocrine, metabolic, and reproductive abnormalities in HIV-positive and HIV-negative women and female youth. The study also aimed to determine possible links between abnormalities and accelerated cellular aging in women and girls.

The larger CARMA cohort study operated from 2008 to 2018. It involved more than 1,000 participants, including women living with HIV (both pregnant and not), their children (both HIV-positive and HIV-exposed uninfected), as well as a control group of HIV-negative women who share socio-demographic characteristics. The researchers sought to determine whether women and female youth living with HIV have an increased risk of hormonal, metabolic, and reproductive abnormality, and whether this correlates to aging at the cellular level.

About The Disease

There is mounting evidence of endocrine, metabolic, and reproductive abnormalities (endocrinopathy) in people living with HIV. These abnormalities increase with age. Two factors thought to be related in endocrinopathy and cellular aging are telomere length and mitochondrial DNA (mtDNA). Telomeres are repetitive DNA sequences that protect the end of our chromosomes. Telomeres naturally shrink as we age, but accelerated shortening can indicate cellular stress. Abnormal levels of mtDNA in the blood can indicate that mitochondria, an important part of our cells, are not functioning properly. In addition, antiretroviral therapy (ART) can affect molecular and cellular aging through a variety of mechanisms. The majority of studies in endocrine and metabolic dysfunction in people living with HIV have primarily been in men, meaning that we do not have a strong understanding of the relationship between HIV, endocrinopathy, and aging in women.

Study Approach

Study participants were women living with HIV and HIV-negative controls 12–50 years of age who had intact ovaries and were enrolled between December 2008 and April 2017 in the Children and Women: AntiRetrovirals and the Markers of Aging (CARMA) cohort. Participants filled out a questionnaire pertaining to personal and family history of endocrine/metabolic or reproductive dysfunction, as well as medications, procedures, or diseases affecting the normal functioning of any of these. Detailed questions regarding menstrual cycles and reproductive histories were also included. Saliva was self-collected by participants to assess late-evening and early-morning hormone levels. A maximum of twenty mL of blood was collected for analysis and comparison between study participants.

Results

Over half of the women living with HIV (WLWH) in CTN 277 had a diagnosis of at least one endocrine abnormality, like diabetes/glucose intolerance, thyroid disorders, or dyslipidemia. Factors associated with the presence of these disorders included increasing age, body mass index, and higher peak viral load. WLWH in this study also developed illnesses earlier in life than their HIV-negative peers, and had very high rates of depression, anxiety, and panic disorders.

Dyslipidemia refers to an imbalance of blood lipids like cholesterol and can lead to heart disease. Compared to people living with HIV, WLWH had higher rates of dyslipidemia, but no differences in other cardiovascular or metabolic risk factors. The average age of this cohort of women was mid-40’s. Telomere length, a measure of cellular aging, was shorter in WLWH but this was not tied to cardiovascular risk. Living with HIV was also associated with lower mitochondrial DNA, another measure of cellular aging. Uncontrolled HIV viremia (high viral load) was linked to loss of telomere length and mitochondrial DNA over time. In WLWH and controls, both markers of cellular aging were associated with tobacco smoking.

Related to pregnancy and family planning, CTN 277 showed that WLWH have lower levels of anti-müllerian hormone (AMH), an important hormone related to ovarian reserve and, as a result, fertility in the later reproductive years. Shorter telomere length was associated with lower level of peak AMH. Compared to the population in B.C., WLWH in the study had lower birth rates. However, younger WLWH had higher birth rates than the general population, while older WLHW had lower rates. Similar to the trends seen in the general population over the past few decades, WLWH are increasingly likely to choose to give birth later in life. Contraception use was similar between the WLWH and controls.

Finally, WLWH did not experience menopause at an earlier age compared to women not living with HIV. WLWH had higher rates of prolonged amenorrhea (lack of menstrual periods) which is an important osteoporosis risk factor. Overall, WLWH had lower bone mineral density than controls, and this was exacerbated by having a history of prolonged amenorrhea. WLWH also consumed less dietary vitamin D than controls, and women with low household income and of non-white ethnicity had the lowest odds of adequate dietary vitamin D intake.

Conclusion

The findings of CTN 277 highlight the importance of maintaining viral control and avoiding smoking to prevent aging-related illnesses in people living with HIV. The study also adds valuable information about telomere length and mtDNA and their role in HIV and aging. The data from this study can help people living with HIV and their caregivers to discuss family planning, and supports the integration of reproductive health into HIV care. This cohort, studied in both CTN 277 and CTN 291, has now been combined with data from CHIWOS (CTN 262) to continue to answer questions about how biological, clinical, and socio-structural determinants of health interact to support healthy aging in women living with HIV (CTN 335).