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Women with HIV: More conference time
Written for NATAP by Judith Aberg, MD, Washington University, Director of HIV Clinic, St Louis
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I do believe women related issues received more attention this year compared with the previous years. Not only were there women specific presentations and abstracts, but also many of the clinical trials evaluating HIV specific therapy or complications of HIV reported differences among the genders. I recommend that you read other NATAP reviews on maternal- fetal transmission, cardiovascular complications and lipodystrophy for gender specific analysis regarding these issues. My focus will be on the differences in pathogenesis of HIV and other diseases based on gender.
One of the foremost questions has been whether men and women can be treated similarly for HIV. Does the natural history of HIV differ among the sexes? Are the transmission risks differently? Are the CD4 count and viral load responses to medications similar?
Contraception May Accelerate HIV Progression. Sagar and colleagues (Abstract 100,Correlates of Viral Diversity in Primary HIV-1 Infection in Women) looked at factors affecting the viral diversity in women early in infection. The investigators had previously shown that the initial HIV-1 proviral population at or near time of seroconversion was a heterogeneous population in 60% of women tested (diverse genetically; virus was mutated). They found no association between the presence of sexually transmitted diseases, demographics or behavioral factors and HIV diversity. However they did report that women with viral diversity were much more likely to have used oral contraception (OR 4.3, 95% CI 1.5-12.8, p<0.006), Depo medroxyprogesterone (OR 4.6, 95% CI 1.5-13.4, p<0.004) or any form of hormonal contraception (OR 4.2, 95% CI 1.8-10.1, p< 0.001) as compared with women that have an initial homogeneous virus population (less viral diversity; less mutated virus). The median of the first viral load measured between 4 months and 12 months post-infection was higher in women with initial viral heterogeneity/diversity (median 100,000, range 3020-1,659,586) as compared to women with homogeneity (median 45,709, range 478-8,511,380) (p=0.02) and this difference persisted in measurements over 5 years post-infection. The median of the first CD4 count measured between 4 months and 5 years post-infection was significantly lower in women with viral heterogeneity (median 394, range 49-978) as compared to women with initial homogeneity (median 460, range 88-949) (p = 0.03) and this difference persisted over 5 years of follow-up. They concluded that hormonal contraception use near the time of infection was associated with acquisition of a genetically complex virus population. An initial heterogeneous virus population is associated with faster disease progression as measured by HIV-1 plasma viral load and CD4 count.
Genes May Confer Partial Protection For Women Against HIV Infection. The human gene for CCR5, a co-receptor on the CD4 cell for HIV-1 attachment , affects susceptibility to infection; people homozygous for a deleted form of the gene, delta 32, are unlikely to be infected; however there have been conflicting results reported among the genders. Phillpot and colleagues (Abstract 118, CCR5 Genotype and Susceptibility to Transmission of HIV-1 in Women) examined the CCR5 genotype of 2047 seropositive and 558 seronegative participants in the Women's Interagency HIV Study, a natural history cohort study of HIV-1 in U.S. women, and examined relationships of CCR5 genotypes to HIV-1 status, ethnicity, transmission risk, disease stage, and response to highly active antiretroviral therapy. The frequency of the CCR5 delta 32 allele was 0.029 -- 0.018 in African Americans, 0.024 in Latinas, 0.068 in Caucasians, and 0.041 for other groups. Although the delta 32 gene frequency was 0.040 for HIV-1-seronegative women, it was 0.026 for HIV-1 seropositives. Analysis of the relationship of HIV-1 infection to CCR5 genotype showed that delta 32 heterozygotes were significantly less likely to be infected, OR=0.63 (95% CI: 0.44-0.90). By contrast, the investigators found no evidence of slowed disease progression or improved response to HAART in heterozygotes. The investigators concluded that the CCR5 delta 32 heterozygous genotype may confer partial protection from HIV-1 infection in women. The delta 32 deletion was much more common in Caucasians than in Africans and Asians. Therefore, this different ethnic susceptibility may play a role in the heterosexual spread of HIV-1 in Africa and Asia.
Higher HIV Viral Load and Lower CD4 Count May Increase Risk for Transmission; Risk Factors for Higher Viral Load. Critchlow and colleagues (Abstract 19, Detection of Human Immunodeficiency Virus (HIV) Type 1 and Type 2 RNA and DNA in Vaginal Secretions among Women in Senegal, West Africa) obtained plasma and vaginal lavage HIV-1 and HIV-2 viral loads to determine if transmission of HIV-1 vs HIV-2 was associated with the amount of HIV in the genital tract at a given stage of HIV disease. Women with HIV-1 (n=170) vs HIV-2 (n=51) were more likely to be younger (31 vs 36 years), unmarried, and present with lower CD4 (301 vs 352 cells/mL) and higher CD8 count (975 vs 676 cells/mL) and more advanced HIV disease. Among women with HIV-1, 82% of vaginal samples were positive for HIV-1 RNA and 50% were positive for HIV-1 DNA. In women with HIV-2, 59% were positive for HIV-2 RNA and 23% were positive for HIV-2 DNA. Vaginal HIV RNA was often found in the absence of HIV DNA, with HIV-1 RNA detected in 73% of HIV-1 DNA negative samples compared to detection of HIV-2 RNA in 53% of HIV-2 DNA negative samples. Further, among women with vaginal HIV detected, >1000 HIV RNA copies/mL were more often detected in women with HIV-1 (46%) than HIV-2 (0%). Factors associated with detection of vaginal HIV RNA among women with HIV-1 and HIV-2 included age >40 years, parity, being divorced or widowed, later disease stage, vaginal pH >5.2, genital infection (HPV, vaginal candidiasis, bacterial vaginosis), increased HIV plasma RNA levels and lower CD4 count, although the magnitude of associations were somewhat less among women with HIV-2. Factors associated with higher vaginal HIV RNA levels were HIV type (HIV-1 vs HIV-2), lower CD4 count, higher plasma HIV RNA levels and vaginal pH. HIV-1 was significantly associated with vaginal HIV RNA level even after adjusting for CD4 count and vaginal pH, although this difference was attenuated after adjusting for plasma HIV level. The investigators concluded that the frequency of HIV detection and the vaginal HIV viral loads were higher among women with HIV-1 compared with those with HIV-2 infection. Higher levels of HIV-1 vaginal viral loads were found in women with lower CD4 counts and may be more likely to transmit virus.
Women May Have Lower Baseline Viral Load Than Men. Current recommendations for initiating HAART are based on CD4 counts and HIV viral loads. These recommendations are based largely on clinical trials in which men were the participants. There have been several studies showing that HIV viral loads are lower in women than men at similar stages of infection, with other studies disputing that finding. Gandhi and colleagues (Abstract 775-W ) addressed the question, "Does Gender Influence HIV Viral Load? by abstracting data from 9 cross-sectional and 4 longitudinal studies. 7 of the 9 cross-sectional studies demonstrated that women had 0.13-0.35 log10 lower HIV RNA levels than men, with women having approximately half the HIV RNA concentrations of men, even upon controlling for CD4 count. In the 4 longitudinal studies reviewed, women had 0.33-0.78 log10 (2- to-6-fold) lower HIV RNA levels than men at similar stages of disease, despite controlling for time since seroconversion. Adjustment for other possible confounders of the relationship between sex and viral load, including age, race and use of antiretroviral therapy, did not change the outcome of lower HIV viral load values in women compared to men in most of the studies. The investigators concluded that women consistently have lower viral RNA loads than men at similar stages of HIV infection, an effect most marked early in the course of infection following HIV seroconversion. Daniel and colleagues (Abstract 776-W,Gender Difference in Early Plasma HIV-1 RNA Levels among HIV-1-Infected African Seroconverters) reported a small study in agreement with the findings by Ghandi and colleagues showing that the baseline VL is lower in women than in men among a heterosexually infected West African population.
Women Appear to Respond The Same as Men to HAART. Accepting that women do in fact have lower HIV viral loads, many questions remain but one would be whether they have the same response on HAART. Wilkin and colleagues (Abstract 777-W) examined "The Effect of Gender on the Long-Term Durability of ART and CD4 Count Rise". The investigators performed a retrospective chart review of all patients attending their HIV clinic who started a first HAART regimen after January 1, 1997. Outcome measures were: having an HIV RNA viral load <400 copies/mL (UVL) within 24 weeks of starting HAART; time from first UVL until virologic failure defined as the first of 2 consecutive viral loads >400 copies/mL; and slope of CD4 change after initiation of HAART. 229 patients were included; 35% were female. The mean baseline CD4 for women prior to starting HAART was 152/mm3 compared to 127/mm3 for men (p=NS). The mean baseline log10 viral load was 4.78 for women and 5.03 for men (p=0.006). The mean time from the first clinic visit to starting HAART was 355 days for women compared to 184 days for men (p=0.03). 7.5% of women failed to reach UVL compared to 19.5% men (OR 3.0, 95%CI 1.2-7.5). Baseline viral load, CD4, use of NNRTI vs PI and age were not related to reaching UVL. The significant factors for failing to reach UVL in the multivariate model were male gender (OR 4.7, 95%CI 1.6-13.9) and HIV risk factor of IDU (OR 3.8, 95%CI 1.2-11.9). The proportion of women maintaining an UVL 1 year later was 79% (95%CI 0.71-0.87) and 3 years later 70% (95%CI 0.60-0.82) and was similar to men. The CD4 change for women after HAART was 122/mm3 per year vs 113/mm3 per year for men (p=.13). Although women were started on HAART with a similar CD4 as men, they had been followed in clinic for a longer period of time before starting HAART. Once starting HAART, women were more likely than men to reach UVL. The investigators did not comment on the role of adherence. Men and women maintained a similar, durable virologic and CD4 response to HAART.
HAART and HPV. Finally, I wanted to briefly mention a topic, which needs much more attention. Human Papilloma virus (HPV) is associated with cervical cancer and HIV-infected women are at higher risk for developing HPV-associated cervical cancer. Conley and colleagues (Abstract119, "Lack of Effect of HAART on HPV DNA Levels in the Female Genital Tract") obtained plasma HIV-1 RNA and vaginal lavage HPV during 345 visits (range 3-17) from 44 HIV-infected women to assess the effect of HAART on HPV viral load in vaginal secretions. In 42 first visits after starting HAART, 11 (26%) increased, 10 (24%) decreased, and 21 (50%) had no change in vaginal HPV DNA loads, while in 237 visits where HAART had not been initiated, 46 (19%) increased, 39 (16%) decreased, and 152 (64%) remained unchanged (p=0.22). For 18 women who were not on HAART, the median vaginal HPV loads, plasma HIV-1 levels, and CD4+ counts at baseline were not significantly different from that at the 2-week or 6-month visits (p>0.05). For 10 women, who had undetectable plasma HIV RNA for at least 6 months after starting HAART, vaginal HPV loads and CD4+ counts at baseline were not significantly different from that at the 2-week or 6-month visits (p>0.05), while plasma HIV-1 levels at baseline decreased significantly at both 2 weeks and 6 months (p<0.05). Their findings indicating that HAART does not have an effect on vaginal HPV viral load suggesting that HAART may not decrease the risk of developing cervical cancer. This is rather disappointing from a clinical viewpoint. It is not consistent with the common belief that the incidence of cervical cancer is decreased among women on HAART. Further studies are needed to explore this association and determine the true prevalence of HPV associated cervical cancer among women with HIV. (editorial note: perhaps nadir CD4 count and viral load prior to starting HAART is related to whether or not HAART affects HPV.
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