Women and HIV/AIDS

Patricia Volkow

Introduction

The opening session of the International AIDS Conference featured an atmosphere overflowing with solidarity and hope, very well expressed by the conference slogan One World One Hope. Hope had grown with the spectacular results of the new combination treatments and the new antriretroviral drugs. For the first time, since the beginning of the epidemic, there is a light that HIV infection might be controlled. This hope soon crashed by the staggering data Dr. Piot(1) mentioned: 22 million men, women and children are living with HIV/AIDS. Every day 8500 people become infected, of which 1000 are children and 40% are women . These data do not represent in any way a hope, neither does the great inequality in the access to antiretroviral treatments and medical care of patients in developed countries compared to patients in developing countries. And much less is this only one world, when boundaries between countries are profoundly marked by the differences in opportunities for education, social and economic benefits. How can we talk of one world, when such differences also separate men and women in two worlds and two realities, even within the same developed countries, not to mention the situation of women in the poorer countries of our planet, where sometimes the only option for economic survival seems to be prostitution. It is, precisely, in this other world of poverty, margination and ignorance where the biological and social susceptibility of women combine to make them more vulnerable to HIV infection. These are the conditions that would place women in the near future to rank first in the number of HIV infected patients if no urgent policies and methods to prevent HIV dissemination are established as a world emergency.

Epidemiological trends

The epidemiological trends presented at the conference highlighted how the HIV/AIDS epidemic has spread more rapidly to weaker economic societies, to minority racial groups in the United States, and to developing countries. The pace of growth of the epdimec among women is greater in any one of the previously mentioned sectors, and now we can see how the cumulative AIDS case ratio (males/females) has decreased in most countries in America. In the United States and Brazil it was 4: 1; in Colombia it was 8: 1 (although there are areas in which the ratio has already decreased to 4: 1); in Honduras it was 2: 1(2-4). In Mexico, a different phenomenon was observed: while the epidemic moved explosively to women in the years from 1987 to 1990, reaching a male/female ratio of 5:1 in four years, related mainly to blood transfusion associated AIDS cases, since 1992 it has reversed stabilizing at a ratio of 6:1 in the last four years(5-7).

The actual dynamics of the HIV epidemic among women is quite similar in the Americas; nowadays women are becoming infected through sexual intercourse(8-10). It seems that as the epidemic grows older the heterosexual transmission becomes more efficient. This is supported by the findings of greater viral load in sexual secretions in patients with advanced disease. In this setting, the possibilities of tnfecting the partner are greater, as has been shown by studies of viral load in the early and late stages of HIV infection(11-13).

Illicit drug users are also one of the groups most affecting women by the HIV/AIDS epidemic, especially in countries where their is a high prevalence of drugs abuse¾ the United States, Brazil, Chile and Argentine. Initially, intravenous drugs users (IV-drug users) were recognized as the second most affected group by the HIV/AIDS epidemic; specific programs for needle exchange and use of bleach were established. New studies presented at the Conference draw attention to another growing group, non-IV drug users, usually crack users. These women had high-risk behavior rendering them more susceptible to HIV-infection, such as money exchanged for sex, inconsistent condom use, and multiple partners. Such studies raise the need to establish specific preventive programs targeted to the population of non-IV drug users. They also serve to alert countries where IV-drug abuse prevalence is low, but where the use of other illicit drugs, smoked or inhaled, is rapidly growing, mainly among adolescents. The use of other non IV drugs might also increase the risk of HIV infection by similar mechanisms described in such users in the United States: money exchanged for sex, inconsistent condom use, no risk perception, etc.(14).

A problem little addressed at the Conference but one that clearly affects women in developing countries was the supply of safe blood. It would seem that this has been guaranteed de facto. But studiess, such as that presented by CDC on Kenya blood supply(15), report that a high percentage of blood is transfused with no screening. Elsewhere, clinical studies conducted in India reported that 75% of AIDS cases in women are secondary to transfusions.(16) It follows that the problem of securing a safe blood supply should continue to be a priority for all countries. In Latin American countries, such as Mexico, the major cause of blood transfusions are gynecological emergencies(17). The experience of Mexico showed that the prohibition of blood commerce had a great positive impact on decreasing the HIV epidemic among women. By contrast, the safe blood supply program carried out by the Nasakero Blood Bank in Kampala, Uganda(18) is an example to follow; it is a centralized program, with well trained and enthusiastic personnel, which works exclusively with voluntary donors and, in a few years, has been able to satisfy the demand for blood in the country. It is evident that Latin American and Caribbean countries need to have similar programs and strict legislation on blood supply, importation and exportation of plasma and its derivatives. The Mexican experience showed the great danger that commercial plasmapheresis represents in the spread of HIV infection in the heterosexual population(7) and the great positive impact that the prohibition of blood commerce had in Mexico. Even though that prohibition was implemented abruptly, there was never any shortage of blood and currently all blood is obtained through voluntary donation.

Areas of interest

At the conference it was evident that the groups of women most studied since the beginning of the AIDS epidemic have been sex workers and women in prenatal care clinics. Works presented at the conference made an urgent call to recapitulate in this sense. Not to abandon such groups but to focus on others who have been omitted. A French group presented a study demonstrating that fertility is diminished in HIV infected women compared to non-infected women(19). This study is of particular interest for countries where seroprevalence studies and therapeutic interventions are solely done in pregnant women, for the case may be that an important portion of affected women might be uncovered.

Studies of trends in women showed that the number of infected housewives in Latin American countries is growing increasingly.. Further research is required to establish preventive strategies to focus exclusively on this sector of the population. If no intervention is done, which, with the data presented at the conference, seems to be urgent, the epidemic would continue to grow in a sector of the population where the perception of risk is minimum.

A collaborative study between a French and an Ethiopian group showed that the risk of HIV infection was higher among a group of female factory workers that used (Depo-Provera). a deposit progesterone injected contraceptive(20). The findings suggested that mucosal changes promoted by progesterone were responsible for the increased risk of infection, in a similar way to findings of studies with primates exposed to progesterone and SIV, where the risk of SIV infection was higher among the group of primates who received progesterone. This study arouses concern in two senses: first, in relation to discouraging the use of contraceptive injections of progesterone, until new studies definitively clatify the risk. The second point is the problem related to parenteral transmission of HIV through intramuscular injections, a topic poorly explored and almost discarded; nevertheless. it is important to recall that Depo-Provera is a 3 ml. injection, which can promote local bleeding, and in places where syringes are reused (a common practice in many developing countries) might constitute a vehicle of HIV infection. An Indian group study conducted in a small community 60 km from Delhi reported an index AIDS case of a women with no risk factors other than intramuscular injections, applied by a private doctor whose clinic was situated 6 km from the community on the highway between Bombay and New Delhi. A seroprevalence survey was condcuted in the rural community and it found 25 more infected cases in the same circumstances to that of the index case(21). The study raises the question of to what extent this mechanism is playing a role in the transmission of HIV in developing countries, where the reuse of boiled syringes is still a reality. We should pay attention to this question, which deserves further investigation in Latin American and Caribbean countries.

Reproductive Health and Sexual Transmitted Diseases

HIV transmission is closely linked to other STDs. The findings of several studies clearly show a large increase in viral load in seminal plasma of patients with gonorrhea, and how viral load diminishes once patients are treated.(22) Similar findings were presented in relation to women genital secretions, who were infected with HIV and STDs(23). Such data force us to reconsider the models of care and detection of STDs and HIV in many countries where they are virtually absent. Examples of care and detection of STDs were presented by Brazil, India and Cameroon(24-26). STDs health-care clinics offer a unique opportunity to educate women, to increase their knowledge of STDs, which is usually very poor, as well as to increase the perception of risk of HIV infection and promote preventive behavior(26-28). These programs should not be based only on one solitary interview for the diagnosis and treatment of STDs; the programs should be structured with information presented through videos, written material and orally by a physician, nurses or social workers, with weekly visits for periods of three or four weeks(29). The information should be clear and in their own language. Examples of this type of intervention were presented for Latino women in the United States, with encouraging results(30).

STDs care models using Pan-American Health Organization STDs guidelines with flux algorithms were presented. The results highlight the necessity to use additional exams, like Gram stain, white cells in genital secretions or wet mount preparations, to increase both sensibility and specificity. Models of centralized care, with relative simple equipment and qualified personnel to evaluate patients and prescribe therapeutic regimes, were proposed. This is especially important in HIV infected women with advanced disease, where the clinical interview and physical exam are insufficient to establish a correct diagnosis of bacterial vaginosis and trichomoniasis(31). The clinical suspicion alone is not enough to establish the correct diagnosis and treatment. The same is true for ulcerative genital disease, where it is even necessary to perform a biopsy in order to establish a correct diagnosis.

There is an urgent need to incorporate the models of detection, prevention and care of HIV/AIDS to the existing schemes for reproductive health care and STDs. These clinics already function in many countries(32-36).

As in the findings published for men with HIV/AIDS, survival of HIV infected women seems to be longer if they are cared for in expert clinics. The impact of survival is even greater for infected women who were studied after 1990. This is probably related to the use of the new antiretroviral and prophylactic treatments. Specialized clinics of experts should be promoted within hospital or community health-care centers, so that HIV patients may be tended to by trained staff(37-38).

Gynecologic pathology

Works presented by different countries showed in an almost unanimous way a higher prevalence of genital Human Papilloma virus (HPV) infection in HIV positive women compared to HIV negative women(39-52). In a similar way, the works showed the close relation between the immune state and the development of cervical dysplasia and invasive carcinoma¾ only one New York group failed to prove it. Genital infection with HPV is not exclusively of uterine cervix; the vagina and vulva can also be affected as well as develop severe dysplasia. The studies highlight the need to conduct an initial complete gynecological exam with colposcopy and cervical cytology and biopsy of suspicious lesions. Subsequent visits each semester with cervical cytology in women with less than 200 CD4 are recommended. The study predicts that the problem of dysplasias and genital HPV related malignancy will increase in the coming years as the number of women who acquire HIV infection through sexual intercourse increases and survives longer. Not only immunologic factors are related to the diagnosis of advanced cervical dysplasia or invasive carcinoma in women. There are social factors that contribute to the late diagnosis of these malignancies, which, it should be stressed, are preventable if diagnosed and treated early. It is urgent to incorporate algorithms for care of this health problem of HIV infected women in the Guidelines for the Clinical Management of HIV Infection in Adults published by WHO, PAHO, or the guidelines existing locally in many countries.

Treatment of HPV lesions in HIV infected women still has not been standardized, although it is known that response to conventional therapy is lower with higher rate of relapses in an inverse relation to CD4 counts. In the near future, if the detection of VPH subtypes 16,18,31 and 45 is incorporated into clinical care, it is possible that an earlier and more aggressive therapy (laser or cryotherapy) of HIV infected women, even without dysplasia, would be recommended, to attempt to eradicate VPH infection in patients with a better immune state. This is an area that needs urgent investigation to answer many important questions.

Antiretroviral pharmacokinetics in women

One of the most repeated questions during the presentation in the conference of the results with the new antiretroviral drugs and combination treatments was its effect and toxicity in women. The answers of most papers presented stress the vacuum of information in this field. Information on pharmacokinetics, on toxicity, on side effects and on the effectiveness in HIV non-pregnant women is very scant. To extrapolate the huge experience existing in the group of male patients to women does not seem correct. The body mass is different and the volume of distribution of many drugs is not the same. The particular effect of such drugs on fertility and on the reproductive system are all questions that need to be answered. Only one study presented gender difference in toxicity and CD4 counts in response to the use of nucleoside analogs was presented. Women’s tolerance to usual doses seems to be lower compared to men, but severe toxicity was greater among men. Women were less tolerant to DDI therapy and ssuoended its use more frequently DDI compared to men, but it was observed that the clinical response of zidovudine in women with higher CD4 counts was substantially better than that in men.(53).

Natural HIV history and related diseases

As in the case of pharmacology studies in women, there is little information on the natural history of HIV or on the evolution of opportunistic infections. One study on CMV corioretinitis showed a worst evolution in women, which was clearly gender-related(54).

The concern raised by the reactivation of toxoplasmosis during pregnancy in HIV-infected women and the risk of congenital infection finds an answer in the work of Lefevre and associates from Paris University. They did not find a higher risk of congenital transmission and they do not recommend prophylactic treatment during pregnancy(55).

A study of the survival of pregnant versus non-pregnant HIV-infected Indian women clearly showed a lower survival in the first group(56,57), contrary to other studies that note that pregnancy does not have a deleterious effect on the natural history of HIV infection(58). Perhaps what is most important of this study is that findings of studies conducted in other countries are not amenable to being extrapolated, as there may be many factors, even social ones, which can contribute to these results.

Female methods of control for the prevention of HIV sexual transmission

The first problem in the prevention of HIV sexual transmission in women is conciousness-raising, so that they identify themselves to be at risk. The second problem is how to protect themselves. Although messages of male condom use as a preventive method for HIV infection may be accessible and clear for women, the possibility to negotiate its use with the partner might be difficult or even impossible, especially in married couples. For this reason, the development of safe, effective and accessible vaginal barriers methods for the prevention of HIV and STDs is urgent and essential in the fight against the HIV epidemic(59). The female condom has shown encouraging results, but is very costly and therefore not affordable by poor women.. What seems to ve very encouraging are the new vaginal microbicides, which are substances that inactivate HIV.

Dr. Cogginso presented a study of preferences of different over-the-counter vaginal spermaticide formulations containing 9-nonoxynol as gel, vaginal film or vaginal tablets conducted in five cities in the United States, Thailand, Ivory Cost, and Zimbabwe. The results showed little irritative effect on cervical and vaginal mucouse with its use; their acceptability was largely conditioned by the partner. The pattern of preferences was very variable. The paper highlighted the need for multiple presentations of the same product to cover the needs of all users and the need to explore in the future the marketing of products promoting STDs prevention, increased sexual pleasure and vaginal health(60).

Perinatal transmission

As the number of HIV infected women increases, perinatal transmission will also increase and it now constitutes a worldwide problem. The percentage of perinatal transmission in different areas varies, from 13% reported in European countries up to 40% reported in African studies. Nowadays, it is accepted that the risk of infection is from 25-to-35% in non-treated women(61,62). Since the ACTG 076 study was published(63, 64), which showed a decrease in vertical transmission from 21% in non-treated women to 8% in patients treated with AZT, great hopes were raised regarding the possibility of being able to prevent perinatal HIV transmission. Studies of the acceptability and impact of this treatment on HIV perinatal transmission in the United States and other countries were presented(65-67).

Doctor Bryson(68) presented an extensive work of risk factors for perinatal transmission known to date and the great advances in the prevention of vertical transmission, although her work emphasized the complexity of this route of HIV transmission, noting that the interventions intended to prevent this mode of transmission are also complex and cannot be limited solely to AZT administration. Her work stressed, moreover, the need to continue further research on questions to answer.

Vertical transmission (pregnant woman to her child) can occur in uterus during pregnancy, at birth and while breast-feeding(69). It can occur as early as at eight weeks of pregnancy and can cause abortion. The factors that determine the risk of transmission to the child are very complex; they include the virus’ own capacity to produce syncithia or not and the viral load (this seems to be critical for determining the risk of transmission). Factors related to the mother include the following: immune stage (CD4 counts), the presence or not of neutralizing antibodies (their relation between neutralizing antibodies/viral load inversely related to the risk of HIV transmission); the stage of HIV disease (as the risk is higher during acute HIV infection and in advanced stages of the advanced disease); the presence of other infections that can compromise placental barrier and promote HIV invasion; and the presence or not of HIV in cervical secretion. Of the conditions related to birth, by cesarean section or natural childbirth, they apparently have no difference in the risk of transmission. What seems crucial is if birth takes place four hours after membrane rupture; the risk of HIV infection is higher after four hours of membrane rupture, and even higher with corioamnioitis. The major risk of infection is during the first pregnancy compared to subseuqent pregnancies. The risk is also higher if invasive procedures are performed, if their is previous placenta, if the child swallows amniotic fluid or blood, or even maternal transfusion to the child at time of birth, or if it is a multiple pregnancy(70-76).

All this knowledge only demonstrates how complex it is to establish preventive treatments for vertical transmission. AZT, if administered starting at 24 weeks of pregnancy in a product infected in uterus in 18th week of gestation, could do nothing to prevent transmission. Equally, zidovutine cannot be administered to women who attend the hospital just before birth, a common phenomenon in many developing countries. In these circumstances, a single dose of nevirapine (a non-nucleoside transcriptase inhibitor), which rapidly crosses the placenta and achieves high blood levels in the baby, might have a protective role.

The transmission through breast-feeding is also a serious problems in developing countries where women cannot count on the safe supply of industrialized milk and hygiene conditions are also poor(77). If an international aid program to assure safe milk supply for children born in poor countries is not established, as has been true of many public-health achievements of this century, Dr. Bryson’s goal of diminishing perinatal transmission to 2% would be attainable exclusively by rich countries. This last point deserves to be considered in Latin America and the Caribbean in creating a program for prevention of vertical transmission, with prenatal AZT administration, expertise obstetric care, and safe industrialized milk supply.

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50. Fruchter, Rachel G, Maiman M, Chapman J, Arrastia CD, Gibbon D, Matthews R, Gates EJ, Remy JC. Is HIV-infection a risk factor for advanced cervical cancer? XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Th.B.4139)

51. Hughes V, Uip D, Reingold A, Hearst N. Hiv infection, vaginitis and cervical neoplasia: implications for clinical care of HIV positive women in Brazil. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Th.B.4140)

52. USA; AIDS Clinical Trials Group. A comparison of gynecologic findings in HIV positive women with CD4 Lymphocyte counts 200 to 500/cc and < 100/cc. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Th.B.4137)

53. Currier S, Spino CS, Grimes J, Cotton DJ. Gender differences in toxicity rates and CD4 responses to nucleoside analogue therapy in ACTG 175. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Th.B.290)

54. Murphy, R., Palella, F., Bonnet, J., Bennett, C., Phair, J. Gender differences in rates of disease progression and survival in patients with AIDS and CMV Retinitis. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (We.C.3413)

55. Lefevre-Elbert Veronique, Ciraru-Vigneron N., Garin J.F., Derouin F., Ravina J.H. Toxoplasmosis serological reactivation and parasitemia in a cohort of HIV positive pregnant women. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada.(We.B.3228)

56. Quinson AM, Mars ME, Ermeneux D, Loi S, Suzan V, Gallais H. Influence of pregnancy and AZT prophylaxis in HIV infected women. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (We.C.3399)

57. Newell ML. PREGNANT HIV INFECTED WOMEN IN EUROPE. (Mo.B.543)

58. Kumar RM, Khuranna A, Uduman S. Impact of pregnancy on maternal AIDS (a prospective study) XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (LB.C.6054)

59. Christopher E. Female-controlled methods to prevent sexual transmission of HIV. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.08)

60. Coggins C. Female-controlled methods to prevet sexual transmissison of HIV. Plenary session, XI International Confernence on HIV/AIDS Vancouver, 9 July 1996.

61. Blanche et al Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery. N Engl J Med 1994; 330:308-12

62. McIntyre JA, Gray GE, Lyons SF. Maternal and obstetrical factors in mother to child transmission of HIV in Soweto, South Africa. (Tu.C.342)

63. Sperling RS, Stratton P, O’Sulllivan MJ, et al. A survey of Zidovudine use in pregnant women with human immunodeficiency virus infection. N Engl J Med 1992; 326:857-61.

64. Zidovudine for prevention of HIV transmission from mother to infant. MMWR 1994 April29; 43:285-7.

65. Simonds RJ, Nesheim S, Matheson P, Abrams E, Vink P, Palumbo P, Steketee R.Declining mother-to-child hiv transmission following perinatal zidovudine recommendations, United States. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.440)

66. Martinez-Tejada B, Coll O, Zamora L, Fortuny C, Ravenau W, Lonca M, Lopez A Zidovudine prophylaxis for the prevention of HIV vertical transmission in the Hospital Clinic of Barcelona. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Mo.B.1130)

67. Landsberger, Ellen J, McGuinness K, Biggers SD.THE Impact of zidovudine on the reduction of perinatal transmission in NYC parturients. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.2595)

68. Bryson Y. Perinatal transmission: associated factors and therapeutics approaches. Plenary session, XI International Confernence on HIV/AIDS Vancouver, 9 July 1996.

69. Dunn Dt, Newell ML, Ades AE, Peckham CS. Risk of human immunodeficiency virus type 1 transmission through breastfeeding. Lancet 1992; 340: 585-8.

70. Lapointe Normand, Samson J, Ag Bazet A, Boucher M, Fauvel M,Tran T, Hankins C. Mother to child HIV transmission associated with duration of the second stage of labour. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada.(Tu.C.340)

71. Wiktor SZ, Ekpini ER, Sibailly TS, Diaby L, Brown T, Fransen K, Steketee R, Coulibaly IM, Laga M, Kalish M, Greenberg AE. The effectiveness of oral zidovudine administered in late pregnancy in lowering plasma and cervicovaginal HIV-1 viral load in hiv-infected pregnant women in Abidjan C`TE D'IVOIRE. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.443)

72. Melvin AJ, Frenkel LM, Cowles MK, Shapiro DE, Watts DH, McCellan C, Mohan K, Burchett S, Bryson YJ, O'Sullivan MJ, Landers D, the Pediatric AIDS Clinical Trials Group An observational study of vertical transmission when the mother but not the infant received oral zidovudine. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada.(Tu.B.2128)

73. Acosta, Maria A, Lupo S, Vitola P, Bortolozzi R, Taborda M.Characteristics of pregnancy in a group of HIV-infected women. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.2569)

74. Duarte G, Quintana SM, Mussi-Pinhata MM, Gir E, Marana HRC, Tess BH.Impact of maternal HIV-1 infection on obstetrical and early neonatal outcome: a nine-year experience. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.2572)

75. Greenberg BL, Semba RD, Vink Peter E, Schoenbaum EE, Farley JJ, Weedon J Serum vitamin a and perinatal transmission of HIV among a cohort of HIV-infected women in the united states. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.2592)

76. Kovacs A, Xu J, Thurston L, Rother C, Rasheed S, Chan L.Effect of maternal viral load on perinatal transmission. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Tu.C.2597)

77. Gray GE, McIntyre JA, Lyons SF.The effect of breastfeeding on vertical transmission of HIV-1 in Soweto, South Africa. XI International Conference on AIDS; 1996 july 7-12; Vancouver, Canada. (Th.C.415)