HIV/AIDS and Maternal and Child Health Programs in

Developing Countries

Paula E. Brentlinger, MD, MPHUniversity of Washington

Department of Health Services; I-TECHFebruary 2007

Today’s Plan

HIV/AIDS prevalence and incidence, mortality

Useful termsHIV transmission and prevention Antiretroviral (ARV) therapyOther considerations in AIDS treatment:

opportunistic infections, duration of ARV effect, ARV compatibility with other MCH initiatives, ethical questions

Part I

HIV incidence, prevalence, and mortality

The HIV/AIDS epidemic (UNAIDS, 2006)

Global Burden of Mortality

Unsafe sex (i.e. unprotected sex with HIV-infected person) recently estimated to be the cause of 25.5% of all male mortality and 30.7% of all female mortality in southeastern Africa

• Ezzati M, et al. Lancet 2002.

Maternal mortality, Africa (Khan, 2006)

The HIV/AIDS epidemic in women

The epidemic in women, continued

“Special attention must be paid to preventing HIV infection within marriages…In rural Uganda, among HIV-infected women aged 15 – 19 years, 88% of the girls were married…”

UNAIDS, Dec. 2004

Maternal HIV status, LBW, and infant survival (from Rollins N et al, 2007)

AIDS and Children (1)

Cause-specific mortality in South Africa (KwaZulu-Natal):

Age group % deaths from AIDS0-28 days 5.0%29 days – 1 year 34.0%1-4 years* 61.0%5-9 years* 33.0%10-14 years* 17.0%

* Most common cause of death in this age groupGarrib A et al, 2006.

AIDS and Children (2)

Pregnancy outcomes and maternal HIV status in South Africa:

OR 1.63 (p==.0015) for adverse birth outcome (maternal death, stillbirth, spontaneous abortions) if mom HIV+.

Source: Rollins N et al 2007

Part II

Basic HIV Glossary

Some useful technical terms

HIV viral load: The quantity/concentration of HIV that is circulating in an infected person’s blood (or other body fluid). The lower the viral load, the healthier and less infectious the patient. Effective antiretroviral treatment reduces (“suppresses”) viral load by a factor of about 10 in the first 2 to 8 weeks of treatment.

CD4 count (aka T-cell count): The quantity of certain infection-preventing white blood cells circulating in an infected person’s blood. High CD4 counts (e.g. over 500) correlate with good resistance to infection. As CD4 counts drop (especially below 200), life-threatening infections become increasingly likely (inevitable).

Glossary (2)

Opportunistic infection (OI): An infection that does not usually trouble a person with a healthy immune system, but that will attack a person with an inadequate (“compromised”) immune system. Also used to describe infections (like TB and malaria) that do occur in healthy people but are much more common in immunocompromised people.

Disease progression: Evolution of HIV infection from no symptoms (pre-AIDS) to mild symptoms (or asymptomatic immunosuppression) to severe disease to death. Takes years in adults, months in infants.

Glossary (3)

ARV: Antiretroviral. A medication specifically designed to prevent HIV from infecting human cells and/or reproducing itself. Many medications now exist, different classes.

HAART: Highly active antiretroviral therapy. Combination treatment with 3 or more antiretrovirals. (Not just any 3, however…) Should be given for the rest of the patient’s life.

Glossary (4)

Vertical transmission: Transmission of HIV (or other infection) from mother to infant.

pMTCT: Prevention of mother-to-child transmission. Antiretroviral regimens used in pMTCT are only given in late pregnancy, delivery, and/or the post-partum period – then they are stopped.

Post-exposure prophylaxis (PEP): Short-course ARV treatment designed to prevent HIV infection in a person who has been accidentally exposed to HIV (by needlestick, transfusion, rape…)

Glossary (5)

Adherence: The extent to which an infected person faithfully takes every single ARV dose as prescribed, measured over long periods of time. Goal is 95% adherence over a period of years.

Toxicity: Medication side effects that can make patients sick, sometimes fatally.

Drug resistance: Adaptation of HIV (by mutation) in such a way as to make the virus partially or completely resistant to the effects of ARVs.

Glossary (6)

First-line regimen: The combination of antiretrovirals given to a patient who has not previously been treated for AIDS. Usually a mixture of 3 drugs from 2 or more different classes. Recommended regimens evolve constantly.

Second-line regimen: ARV regimen given to a patient who has not responded to (failed) or not tolerated a first-line regimen.

And so on….

Part III

HIV transmission, HIV prevention

Transmission of HIV

Sexual: Consensual, commercial, rape. Blood and blood products: Blood or blood

product (e.g. clotting factors for hemophiliacs) transfusions, needlesticks in hospitals, needle sharing by IV drug users

Vertical: Transmission from mother to child during pregnancy, delivery, or subsequent breast-feeding.

Combinations of the above: various

HIV Transmission Query

Which is riskier, having unprotected intercourse with an HIV+ person, or being

born to one?

Risk of Transmission, Quantified

Needlestick injury (e.g. to health worker): 3/1000 incidents (0.3% per incident).

Unprotected receptive vaginal intercourse 0.1 – 0.2% per sexual act (on average! see below).

Infant born vaginally to HIV+ mother (from pMTCT trials, no breast-feeding): 18.9% to 25.5%. (i.e. approximately 100x riskier than sex…)

Blood transfusion: 95% per transfusion of infected blood

Sexual transmission of HIV (Wawer 2005)

HIV transmission and STIs (from Cohen and Pilcher, 2005)

How to interrupt transmission (1)

Sexual: Abstinence, “Be faithful”, Condom use, “safe sex”, deferral of 1st sexual encounters (in youth), monogamy (including serial), screening of commercial sex workers and other high-risk groups, control of rape, post-exposure prophylaxis (PEP), antiretrovirals (ARVs)

Vertical: ARVs for Mom (and infant?), c-sections, avoidance of breast feeding (???)

Population-level correlates of HIV transmission

In an analysis of 81 variables and HIV seroprevalence in 122 developing countries, the following were associated with higher HIV prevalence:

Younger age at 1st sexual encounter, increased teenage birth rates, increased fertility rates, decreased contraceptive use, increased casual sex, increased herpes prevalence, fewer doctors, less access to essential medications…

Drain P et al, J AIDS 2004

How to avoid transmission (2)

Blood and blood products: Screen the blood supply, avoid unnecessary transfusions, decrease the need for transfusions (malaria and hookworm control, better obstetrical practices), universal precautions (gloves!), needle exchanges or bleach for intravenous drug users (IVDU), PEP, safer obstetrical practices (e.g. avoid episiotomies…)

How to interrupt transmission (3)

Prevent and/or treat infections that result in increased HIV viral load (herpes, syphilis, TB, malaria….)

Abu-Raddad et al (2006) estimate: Kisumu, Kenya (pop. 200,000): 8500 excess HIV infections caused by malaria-related HIV viral load increases between 1980 and 2005!

How effective is prevention?: Condoms (1)

Some successful targeted condom promotion programs:

• Targeted condom promotion (condom distribution plus individual and group counseling) in female commercial sex workers in Kenya. Condom use associated with threefold reduction of risk of HIV seroconversion.

• Condom use and HIV education in female sex workers in India led to decreased HIV incidence (by about 67%) in intervention group.

• Targeted condom distribution and HIV education in male army conscripts in Thailand led to 50% reduction in HIV incidence.

Merson M, et al. AIDS 2000.

Condoms (2)

In one study in Nicaragua, provision of free condoms to users of rent-by-the hour motels only led to condom use in 62.1% of (presumed) commercial sexual encounters and 24.5% of non-commercial sexual encounters. Addition of educational materials actually decreased condom use slightly – odds ratio for condom use (commercial sex) when health education was also provided was 0.89 (95% CI 0.84 – 0.94).

Recent review of interventions to promote condom use: Effect range (“reduction in non-use of condoms”) ranged from 1% to 57%, depending on strategy and target.

Egger M et al. Lancet 2000. Stover J et al, Lancet 2002.

How effective is prevention?: Voluntary Counseling & Testing (VCT)

Random assignment of individual or couple participants to VCT vs. health education alone in Kenya, Tanzania, and Trinidad. Outcome was reduction of unprotected intercourse with non-primary sexual partners (not reduction of HIV transmission). In men, 35% reduction with VCT vs. 13% with health education alone; in women 39% vs. 17%. Counseling visits were unlimited before and after HIV testing. Subsequent seroconversion of HIV-negative not reported.

The Voluntary HIV-1 Counseling and Testing Efficacy Study Group. Lancet 2000;356:103-112.

VCT (2)

Some aftermath of VCT: Of HIV+ male subjects who tested individually and subsequently disclosed their status to a partner:

17% reported the breakup of a marriage, 60% reported the breakup of a sexual relationship, 10% reported physical abuse, and 8% reported being neglected or disowned by family (vs. 3%, 30%, 2%, and 0% of HIV-negative who disclosed.). For women who were HIV+ and disclosed: 14% break-up of

marriage, 26% breakup of sexual relationship, 7% physical abuse, 3% neglected or disowned by family (vs. 1%, 14%, 4%, and 2% if HIV-negative and disclosed).

Grinstead O, et al. AIDS 2001.

VCT (3)

One meta-analysis of effectiveness of HIV counseling and testing for reduction of risky sexual practices concluded, “HIV counseling and testing appears to provide an effective means of secondary prevention for HIV-positive individuals but, as conducted in the reviewed studies, is not an effective primary prevention strategy for uninfected participants.”

Weinhardt et al, Am J Pub Health 1999. [i]

VCT (4)

Recent study of effect of VCT on sexual risk behavior and HIV acquisition in Rakai, Uganda, concluded:

“In this rural cohort where VCT services are free and accessible, there is self-selection of individuals accepting VCT, and no impact of VCT on subsequent sexual risk factors or HIV incidence.”

Matovu J et al, AIDS 2005.

Risks vs. Benefits of HIV Testing

Presumed Risks: Stigma, Discrimination, Depression, Violence

Presumed Benefits: Access to Treatment,

Behavior Change

Risk vs. Benefit equation differs by site and by individual! (more on this later)

How effective is prevention? Health education (1)

In Uganda, HIV seroprevalence in pregnant women dropped 54% during a period in which there was active HIV/AIDS education (the ABCs) and involvement with multiple sexual partners dropped 60%.

In Kenya, Zambia, and Malawi: Similar rates of abstinence and condom use, but high proportion with multiple sexual partners. No equivalent decrease in seroprevalence.

Stoneburner RL, Low-Beer D. Int J Epi 2004 May.

Re the gap between knowledge and behavior…

Raise your hand if you have ever known a university-educated person who got pregnant or fathered a baby unintentionally.

Raise your hand if you have ever known a university-educated person who knowingly had sex with someone who was “high-risk.”

How effective is prevention? Antiretrovirals for PMTCT (1)

Monotherapy with zidovudine (AZT) reduced HIV transmission during pregnancy and childbirth by 67% (25.5% with placebo vs. 8.3% with zidovudine) in PACTG 076 trial. Similar or greater reductions with other perinatal regimens using 1 or more ARVs.

• Connor E, N Engl J Med 1994.

Impact of ARVs for pMTCT, by regimen,for the infant (PMTCT 2)

Zidovudine only (IV in labor, 6 wks post-partum): 10% transmission, vs 27% if placebo (62% reduction)

ZDV/3TC (orally in labor, 7 days post-partum) : 9%, vs. 15% if placebo (42% reduction)

Nevirapine (single oral dose in labor, 1 dose post-partum): 12%, vs. 21% with short-course ZDV (47% reduction)

ZDV/NVP (6 weeks ZDV+single-dose NVP intrapartum; 6 wks post-partum: 1.1%, vs. 6.6% for ZDV alone (83% reduction)

HAART plus caesarean section: 1-2%

Sources: various, including DHHS guidelines, conference abstracts

Note on duration of pMTCT regimens (PMTCT 3)

Shortest: Single dose of NVP for mom in labor, followed by single dose of NVP for newborn.

Longest: HAART started early in pregnancy and continued indefinitely thereafter (but this is actually a treatment regimen, not just a prevention regimen).

Implications of difference: Financial, logistical, effectiveness….

Recommendations change frequently.

PMTCT (4)

After perinatal nevirapine was implemented in “a real-life situation” in Kenya, investigators found that “The perinatal HIV-1 transmission rate at 14 weeks was 18.1%, similar to the 21.7% before the intervention (RR 1.2, 95% CI 0.78.1.84). These data call for further evaluation of the simple nevirapine regimen in field conditions…”

Quaghebeur A et al, AIDS 2004.

PMTCT (5)

Short-term use of antiretrovirals to prevent vertical transmission may induce HIV drug resistance and/or drug toxicity, which may in turn restrict maternal or infant HIV treatment options later on.

PMTCT (6): Drug resistance

Mashi study, Botswana:6-month likelihood of ARV failure in moms:

AZT + 1-dose NVP: 18.4%AZT alone: 5.0%

If woman started ART < 6 months PP:NVP + AZT 41.0%

AZT alone 0Starting ART > 6 months PP

NVP+AZT 12.0% AZT alone 7.8%Source: Lockman et al 2007

PMTCT (7): Drug resistance, cont’d

Mashi study results for infants:

Virologic failure at 6 months of HAART:

AZT+ NVP 76.9%

AZT alone 9.1%

PMTCT (8): Drug toxicities

Of pregnant women in Maputo, Mozambique, on 3-drug PMTCT regimens:

Liver toxicity in 8% (5% moderate, 3% severe).

Skin toxicity (SJS – severe) in 3%

Moderate to severe anemia ( in women without anemia at baseline): 20%

Switched or stopped regimens during pregnancy because of toxicity: 8%

Source: Jamisse L et al 2007

PMTCT (9)

PMTCT regimens are STOPPED after delivery (or pregnancy loss); their purpose is to prevent vertical transmission, not to improve the health of the mother.

How effective is prevention? Breast vs. bottle-feeding

Botswana (Mashi) data again:

Breast Formula

HIV at 7 mos.* 9.0% 5.6%

Mortality at 7 mos.** 4.9% 9.3%

HIV or mort. 18 mos*** 13.9% 15.1%

p=.04; ** p=.003; ***p=.21Source: Thior et al 2006

How effective is prevention? The case of Brazil

Aggressively advertised, nationwide:Free antiretroviral treatment, needle-exchange campaigns, condom campaigns, explicit campaigns to prevent HIV in sex workers, MSM, prisoners, IVDU.

Result: HIV seroprevalence declined from 1.5% (early 90s) to 0.6% by 2000; subsequently stable.

Compare to South Africa: HIV seroprevalence 1.5% in early 90s; 35% in pregnant women by 2005…

Source: Okie S. 2006

5 basic conclusions re HIV prevention

1. It is imperative that we prevent HIV infection.2. What works in the research setting may not work in the

field, or in a different context.3. Prevention interventions must be tailored to local

circumstances.4. Some prevention programs carry risks (of stigma,

discrimination, drug resistance, etc) to participants; these must be weighed against benefits.

5. Thus far, our prevention efforts have failed millions of people: EXCEPT in Brazil (and other Brazil-like settings) – where political will and the integration of prevention and treatment did work!

Questions for group work

1. In “your” country, could Brazil’s approach be implemented?

2. If not what are the principal obstacles?

(Discuss for 5 minutes, then we will list.)

Part IV

HIV treatment.

Broad definition of HIV treatment

3 principal components

a. Antiretroviral treatment

b. Prevention, diagnosis, treatment of related infections

c. Social and nutritional support; advocacy

Basic concept of ARV treatment

ARV treatment is meant to suppress HIV viral load. Where viral load is reduced, HIV is prevented from attacking the human immune system, the immune system (and the patient) recover from the worst effects of HIV, evolution of drug resistance is hindered, and less HIV is present in potentially infectious body fluids.

Impact of HAART in Developed Countries

In US, Canada, Europe: Survival 10 years after infection, by age of patient:

Pre-HAART era HAART era

16-24 years: 64% 94%25-34 years: 56% 95%35-44 years: 42% 91%>45 years: 28% 87%

Source: CASCADE Collaboration (Porter K), 2003

Note re success of HAART in developed countries

In general, patients on HAART in developed countries also have:

Access to food

Access to safe drinking water

Access to effective medical interventions for prevention and treatment of OIs

Little exposure to malaria, TB, cholera, etc.

Impact of HAART in Brazil

Median survival of adults after AIDS diagnosis in Brazil, by date of diagnosis:

1980s: 5 months

1995 (pre-HAART): 18 months

1996: (HAART era): 58 months

Risk of death in pts on HAART only 6% of rate in pts receiving no ARVS

Source: Marins J et al, 2003.

Impact of HAART in South Africa

Medecins sans Frontieres project in Khayelitsha: Of 1st 287 patients started on HAART,

86.3% still alive at 24 monthsMedian CD4 count gain 288 at 24 monthsViral load < 400 copies/ml in 69.7% of

patients at 24 months

Coetzee D, et al. AIDS 2004.

Summary of known benefits of ARV treatment

98% of mother-to-child HIV transmission can be prevented with existing regimens (and replacement feeding where possible).

Lifespan of HIV-infected persons can be increased by many years.

Quality of life of HIV-infected persons can improve dramatically; some actually climb out of the sickbed and go back to work.

But: ARVs are not a panacea

HAART does NOT eliminate competing risks for mortality and morbidity – e.g. diarrhea, pneumonia, malaria, TB, malnutrition, eclampsia, or obstetrical hemorrhage – although incidence of many infections may decrease as HAART treatment restores immune function.

HAART is NO substitute for food, housing, or live parents.

HAART does not cure AIDS. (HIV is not completely eliminated by treatment.)

The early-phase mortality gap (from

ART-LINC, 2006)

Limits of ARV Treatment, 1: Duration of response to ARVs

Some patients remain on same ARV regimen for years, and are clinically stable. However:

On average (per US guidelines): “Virologic failure [defined as viral load >400 copies mL at 24 weeks, .50 copies at 48 weeks, or rebound to >400 after suppression] occurs in as many as 63% of patients in population-based studies…Immunologic failure (i.e. return to baseline CD4 cell count) occurred an average of 3 years following virologic failure in patients remaining on same antiretroviral regimen…

Duration of response, continued

In one study, clinical progression (a new AIDS event or death) occurred in 7% of treated patients with suppressed viremia, 9% of treated patients with suppressed viremia followed by viral rebound, and 20% of treated patients who never achieved suppressed viremia over 2.5 years. Some patient cohorts demonstrated that suboptimal adherence and toxicity accounted for 28-40% of treatment regimen discontinuations.”

DHHS 2003 guidelines

Limits of ARV Treatment, 2: Timing of HAART initiation

If HAART is begun “too early” in the course of HIV infection (e.g. in asymptomatic persons with high CD4 counts), the combined effects of drug toxicity and drug resistance can “use up” the patient’s best treatment options before the patient becomes significantly ill from AIDS.

When is “too early” vs. “too late”? Opinions differ, especially in regard to patients who are clinically healthy. But there is consensus that patients who are truly sick from AIDS should start HAART.

Hazards of ARV Therapy

3 important classes of ARV hazards (aside from cost in time and money):

1. Drug toxicity and drug interactions (related)

2. Drug resistance

3. Immune reconstitution syndromes

Important Drug Toxicities

Nevirapine (NVP) can cause fatal liver toxicity, especially in female patients with high CD4 counts (e.g. most pregnant women) and/or hepatitis co-infection.

11% of women with CD4 counts >250 thought likely to develop significant liver toxicity with long-course NVP.

NVP can also cause potentially fatal rash-related reactions, such as Stevens-Johnson syndrome. NVP toxicity overlaps toxicities of co-trimoxazole and sulfadoxine-pyrimethamine (Fansidar).

However: Toxicity rare (resistance a bigger problem) with single-dose NVP for pMTCT.

Common Drug Toxicities, continued

Zidovudine (ZDV, AZT) can cause significant anemia.

Didanosine (DDI) and stavudine (D4T) have caused fatal lactic acidosis in pregnancy when given in combination.

Stavudine commonly causes peripheral neuropathy.

Important data gaps on drug toxicities

We do not yet have enough data to describe the long term effects on children of in utero exposure to antiretrovirals. At present, it is assumed (and seems obvious) that the known, immediate risks of vertical HIV transmission are far greater than the largely theoretical risks of long-term side effects (such as carcinogenicity).

Resistance

Clinically significant antiretroviral drug resistance is largely the result of antiretroviral treatment.

Resistance to antiretrovirals occurs primarily in patients who do not take their medications regularly (95% adherence thought necessary to prevent resistance) and in patients who are prescribed inadequate regimens (e.g. only 1 drug, or inadequate doses of 3 drugs, or wrong mixtures of drugs, or intermittent drugs).

However, resistance also occurs in adherent patients taking proper regimens.

Conditions Predisposing to AIDS Progression: Poor Adherence to

Antiretrovirals

Survival vs. adherence: Mortality rate 15.2% in patients adherent to fewer than 75% of HAART doses, vs. 4.1% in patients adherent to 95% or more of doses.

• Wood E et al 2003 .

ARV Adherence and Resistance

• Between 1995 (when HAART was introduced in US) and 2000, prevalence of drug resistance in antiretroviral-naïve patients (implying presence of resistance at time of transmission of HIV) increased from 3.4% to 12.4%.[i] Patients infected with highly resistant strains of HIV appear to respond more slowly to antiretroviral therapy.

• [i] Little S, et al. N Engl J Med 2002.

Consequences of ARV Resistance

Patients who develop resistance to 1 member of a given class of ARVs often have cross-resistance to other drugs in the same class. This (along with cost of 2nd line drugs) limits their future drug choices (and hence their survival).

Patients who develop resistance appear to be at higher risk of dying and of developing AIDS complications.

Resistant strains of HIV can be transmitted to sexual partners and to newborn infants, thus potentially limiting treatment options in others (or in whole population).

Important note on drug resistance and short-course pMTCT

Women who take single-dose NVP to prevent MTCT are likely to develop NVP-resistant HIV (38.8% in 1 South African study). These women will respond less well to HAART (34% response with NVP resistance vs 75% response if no NVP exposure) if they start HAART within 6 months or so (exact risk period unknown) of delivery. Unclear how long this resistance lasts at important levels, however.

But - Limited courses of AZT for prevention of perinatal HIV transmission produce little AZT resistance in the mother.

Sources: Martinson et al 2004; Jourdain et al 2004

Potential contributors to development of drug resistant HIV

ARV supply at health facilities is inadequate or arrives irregularly.

Patients cannot afford to buy their drugs, or cannot afford visits to health facility or pharmacy.

Patients are afraid that other people will see them when they visit the HIV clinic or pharmacy, or when they are taking their drugs.

Health care workers fail to understand the importance of adherence, and do not prepare patients properly for good adherence.

More potential contributors to poor adherence and resistance

Patient develops active tuberculosis and stops ARVs because they are incompatible with TB regimen. No alternative ARV regimen available.

Patient moves in and out of region to seek employment; no AIDS follow-up or medications available at work site.

Patient shares pills with HIV-infected spouse or friends. Or sells them.

More contributors to drug resistance

Pregnant patient is nauseated; doesn’t take pills.

HIV-infected child’s untreated parents die of AIDS; nobody around to supervise therapy (or feed the child…).

Neither patients nor health workers understand the principles of chronic disease therapy; believe that short course will “cure” AIDS.

More contributors to drug resistance

Patients are prescribed confusing regimens that require them to take multiple pills 6 times a day, some on an empty stomach, some with food…

Patient hears on the radio that a mixture of garlic and olive oil is just as good as HAART.

The region’s one good AIDS clinician dies of multi-drug resistant TB (caught from a patient).

The NGO’s contract ends and the AIDS program closes.

Strategies for improving adherence

Jelly beans, co-trimoxazole, or other “practice” regimens

Educate patients (and families?) and establish adherence readiness before starting therapy

Written medication schedules, pillboxes, alarms, pagers, the buddy system

Directly observed therapyTalk to your colleagues about TB experience!

Read the TB literature!Respect privacy/confidentiality/stigma concerns.Fight against stigma.

An aside re adherence and TB drug resistance in New York City

The City of New York used the following aids to encourage TB treatment adherence:

Home visits by community health workers, subway tokens, McDonald’s hamburgers, birthday cakes, trips to amusement parks, and (very rarely) incarceration.

This combination of bribery and occasional coercion worked to control an outbreak of multi-drug resistant TB in New York.

Can your program afford it???

Immune reconstitution

HAART restores the function of the AIDS patient’s immune system over a period of weeks to months. This process is known as immune reconstitution.

Because the manifestations of many diseases are caused by immune reaction to the disease, immune reconstitution can cause disease symptoms to flare. Sometimes hard to distinguish from disease progression or drug toxicity (or symptoms of pregnancy). Fortunately, does not occur in most patients.

Important examples: TB, viral hepatitis, pre-eclampsia (?), Kaposi’s sarcoma (?).

Questions for group work (2)

1. In “your” country, what is the greatest obstacle to nation-wide rollout of ART for women and children?

2. What would be the most practical and effective means of overcoming this obstacle?

Again: Discuss for 5 minutes, then report.

Part V. Other considerations

Management of opportunistic infections

Malnutrition

ARV compatibility with other MCH initiatives

Equity and ethical questions

Opportunistic infections

3 important issues:OIs (and other infections) can increase HIV viral

load, thus increasing risk of HIV transmission (e.g. mother-to-child in presence of malaria [probably]) or disease progression (as in TB)

In general, persons with AIDS die of complications of infection, not HIV itself.

Malnutrition increases susceptibility to many infections. Episodes of infection make malnutrition worse. Good OI management may require food supplements.

TB and AIDS

Prospective study of HIV disease progression vs. TB in Cape Town (South Africa): “The median time of progression to AIDS, in patients free of AIDS at baseline, was 6 months for tuberculosis cases compared with 14.5 months for the comparison group (p=0.05).”…”…multivariate Cox proportional hazards regression revealed that… tuberculosis conferred an increased independent risk of death in HIV-infected patients (RR=2.16, 95% CI 1.29-3.59, p=.003).” [i] TB is the most commonly reported cause of death in South Africans with AIDS. (Note: but it is 97% treatable!)

• Badri M, et al. Int J Tuberc Lung Dis 2001.

Concurrent Infections and AIDS II: Malaria

Incidence rates of P. falciparum malaria 57 per 1000 person-years in HIV+ persons with CD4 counts >500, vs. 140 in persons with CD4 counts <200, p<.001. (Prospective cohort study in Uganda.)

French N, et al. AIDS 2001.

OI management should accompany ARVs

In healthy HIV+ pregnant women: Need to control malaria.

In persons with symptomatic AIDS: Screen for latent and active TB before starting HAART. If active TB, consider deferring HAART until TB is treated. WHO and others recommend daily prophylactic co-trimoxazole to prevent bacterial infections of lung, gut, and skin, and to prevent malaria (where susceptible). Give insecticide-treated bednet if in malaria-endemic area.

Watch nutritional status, including anemia.

Co-morbid Conditions and AIDS: Malnutrition

Protein-energy malnutrition (PEM) and micronutrient deficiencies both interfere with human immune function.

Global Burden of Disease study: Underweight is estimated to cause 15.4% of all male and 14.7% of all female deaths in southeastern Africa. So, unsafe sex + malnutrition cause 40-50% of all deaths…

Malnutrition/Infection: Classic Studies

Illness of children aged 0–58 mo in two Guatemala highland Indian villages, one with daily supplementary feeding and one with daily medical care. Scrimshaw and Guzman, 1995.

Santa Maria Cauqué Santa Cruz Balanya Medical treatment village Supplementary feeding village

Year Illnesses per child Illnesses per child

1960 3.4/y 1.3/y1961 4.7/y 1.3/y1962 5.9/y 1.4/y1963 4.7/y 2.6/y1960–1964 18.7 in 4 y 6.6 in 4 y

Micronutrient supplementation and HIV

Conflicting data on Vitamin A:Antenatal Vitamin A increases risk of MTCT

in Tanzania, decreases in S.Afr&Malawi!

Better data on multivits:Reduced disease progression and death

mortality in HIV/TB pts, and fewer adverse pregnancy outcomes in Tanzania

Source: Friis, 2006

Compatibility of ARV therapy with other MCH initiatives

4 types of concerns:

• Special considerations re ARV use in women and children

• Drug policy questions

• Systems issues

• Algorithm issues

Special considerations re ARV use in women

Some ARVs are probably teratogenic (based on animal studies) and should not be given in pregnancy or to women at risk of pregnancy.

Some ARVs appear to have increased toxicity in pregnancy (e.g. DDI and D4T in combination).

Some ARV side effects more common in women (e.g. nevirapine rash and hepatotoxicity).

Special considerations re ARV use in children

Conventional HIV tests can’t be relied upon until approximately 18 months of age.

Need liquid formulations of drug (expensive!).

Frequent readjustments of drug dose to adjust for changing weight and immune function.

Nutritional support for child.

Is there a healthy adult at home to administer the drugs?

Screen parents for TB…

More considerations in children

Normal range of CD4 counts varies by age in children.Risk of disease progression is highest in the youngest

children: 20-25% progress to symptomatic AIDS or death by 12 months.

Little information on optimal drug doses for babies. Controversy re best time to start HAART in infants: At time

of diagnosis, at age 12 months, or only when symptomatic?

See: DHHS guidelines for pediatric AIDS treatment

Drug policy questions related to MCH and ARVs

Prophylactic co-trimoxazole (CTX):1. Should pregnant women on prophylactic CTX and/or therapeutic

NVP also receive Fansidar (SP) for malaria prevention? (Problem: overlapping toxicities, antimalarial drug resistance)

2. If CTX is the national 1st line drug for pneumonias and urinary tract infections, what should you give the sick child who is already on prophylactic CTX? (Problem: drug resistance)

3. If syndromic management of STIs is the norm and regimen contains CTX, what about patients who are already on it? (problem: over-medicating)

More drug policy questions

Rifampin:• If the national 1st line regimen for TB treatment

contains rifampin, should an alternative (probably more expensive) HAART regimen be available for HIV-infected TB patients? (Problem: drug interactions)

ARVs:1. AZT: If pregnant women in your area already have a

high prevalence of anemia (thanks to malaria and hookworm), is AZT the best drug for pMTCT? (problem: drug side effects)

2. NVP: If HAART is about to become available in your area, should pregnant HIV+ women still get single-dose NVP for pMTCT? (problem: drug resistance)

More drug policy questions

No published data on interactions or overlapping toxicities between ARVs and newer combination antimalarials (e.g. Coartem). If you are aware of any data please raise your hand!

Systems issues (aside from $ and drug supply and training…)

How to identify HIV+ women in labor so that they can receive NVP (or other medication/intervention) without compromising privacy?

If a woman receives prenatal care at 1 site and HIV care at another, how to coordinate? (Will the HAART prescriber know that prenatal clinic just gave Fansidar? Or will rash with liver failure be the first clue?)

Should sick HIV+ children be seen at HIV clinic or in the usual IMCI site?

Algorithm/guideline issues

IMCI: Does existing IMCI algorithm in your country include questions on child’s (or mother’s) HIV status, use of prophylactic CTX, etc? Does algorithm accommodate broader differential diagnosis of key symptoms (cough, fever..) in HIV+ children?

Malaria control: Are HIV+ persons considered a bednet target group, along with pregnant women and young children?

Equity and ethical questions

Where resources do not permit all HIV-infected persons to be treated, who gets treated? Who is left to die?

Where resources do not permit all important health initiatives to be implemented, which initiatives will be dropped (or not allowed to expand) in order to supply ARVs?

What about your own HIV-infected staff?

pMTCT-related ethical quandaries

Should you create a large population of women (or others) who know that they are HIV-infected in a setting where AIDS is highly stigmatized and there is no HAART available?

If HAART will be available soon, should asymptomatic HIV+ pregnant women run the risk of developing ARV-resistant HIV before they start real treatment?

Is it fair to give pMTCT regimens only to women who are willing to have HIV testing and to know their own HIV status?

Questions for group work (3)

1. In “your” country, what is the greatest inequity resulting in increased HIV transmission and/or decreased access to HIV treatment for women and children?

2. What would be the most effective means of overcoming this inequity?

Discuss for 5 minutes, then report.

Further reading:

See handout for selected references. Note that the literature evolves constantly!

Thanks, Mary Anne!

If you have further comments, anecdotes, references, or (especially) corrections,

please send them to me at:

brentp2@u.washington.edu

(This is a work in progress.)

References

See accompanying document (too many to fit here)

Fin. Fim. The End.