2. AIDS story till now
India managed to reduce its HIV count by a staggering
57 % while both Bangladesh and Sri Lanka saw an
increase in HIV cases by 25 %(2001-11). This has led to
various international figures praising India’s HIV/AIDS
prevention model
PLHIV
57 Lakh(2001)
21 lakh(2011)
Adult(15-49 years)
Prevalence
0.41 %(2001)
0.27%(2011)
Source : NACO Dec 2013 Report
3. Still a long way to go
• PLHIV Estimates as of 2011
– South Africa - 5.6 million
– Nigeria - 3.3 million
– India - 2.1 million
Source :UNAIDS Report on the Global AIDS epidemic 2013
A mere 0.1% increase in the HIV prevalence would
increase the estimated number of people living with HIV
by over half a million.In India 90% of the
people with an unmet need for antiretroviral treatment
live
5. Contents
• AIDS Epidemiology
• Continuum of care
• HIV Testing and Counseling
• Anti-Retroviral Therapy (ART)
• HIV in Pregnancy
• HIV-TB co-infection
• HIV Vaccine
• NACP- IV
• References
7. AIDS: Epidemiology
• Concentrated HIV epidemic: HIV has spread
rapidly in one or more defined subpopulation but is
not well established in the general population.
– Numerical proxy: HIV prevalence is consistently over 5%
in at least one defined subpopulation but is less than 1%
among pregnant women.
• Generalized HIV epidemic: HIV is firmly
established in the general population.
– Numerical proxy: HIV prevalence consistently exceeding
1% among pregnant women. E.g –SubSaharan Africa
8. • Mixed epidemics: people are acquiring HIV
infection in one or more subpopulations and in the
general population. Mixed epidemics are therefore
one or more concentrated epidemics within a
generalized epidemic. e.g – Nigeria, Rwanda
• Low-level epidemic: epidemics in which the
prevalence of HIV infection has not consistently
exceeded 1% in the general population nationally or
5% in any subpopulation.
AIDS: Epidemiology
9. • ART settings acc. to uptake of ART
– Low-uptake ART settings – uptake less than 50%
– moderate-uptake ART settings - uptake 50-80%
– high-uptake ART settings - uptake greater than
80%
( uptake of ART among those eligible for ART )
AIDS: Epidemiology
10. Epidemiology
• Concentrated HIV epidemic: HIV has spread rapidly in one or more defined
subpopulation but is not well established in the general population. Numerical
proxy: HIV prevalence is consistently over 5% in at least one defined
subpopulation but is less than 1% among pregnant women in urban areas.
• Generalized HIV epidemic: HIV is firmly established in the general population.
Numerical proxy: HIV prevalence consistently exceeding 1% among pregnant
women. Most generalized HIV epidemics are mixed in nature, in which certain
(key) subpopulations are disproportionately affected.
• Mixed epidemics: people are acquiring HIV infection in one or more
subpopulations and in the general population. Mixed epidemics are therefore one or
more concentrated epidemics within a generalized epidemic.
• Low-level epidemic: epidemics in which the prevalence of HIV infection has not
consistently exceeded 1% in the general population nationally or 5% in any
subpopulation.
• Low-, moderate- and high-uptake ART settings refer to settings in which the
uptake of ART among those eligible for ART is less than 50%, 50–80% and greater
than 80%, respectively.
The magnitude of the problem can be assessed from the
fact that for every person who gains access to anti-
retroviral drugs, two people are newly infected with HIV
11.
12.
13. Declining Trends of HIV Epidemic in India
22.5 21.9 21.4 21.1 20.9
0.33
0.31 0.30
0.28 0.27
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.0
5.0
10.0
15.0
20.0
25.0
2007 2008 2009 2010 2011
AdultHIVPrevalence(%)
NumberofPLHIV(Lakhs)
Estimated Adult HIV Prevalence & Number of PLHIV, India, 2007-11
Number of PLHA (Lakhs) Adult HIV Prevalence (%)
Female: 39% of PLHIV; Children: 7% of PLHIV
Source: Technical Report India HIV Estimates 2012, NACO & NIMS
14. Key terms in HIV Epidemic
HIGH RISK GROUP
Female Sex Worker(FSW)
Men who have Sex with
Men(MSM)
Transgender
Injecting drug users(IDU)
VULNERABLE
POPULATION
Women having casual
partners
Spouses of high risk groups
Youth
BRIDGE POPULATION
Migrant
Truckers
KEY POPULATION
HRG
Vulnerable Population
PLHA
15. Indian epidemic: Characteristics
• India’s highly heterogeneous epidemic is largely concentrated
in only a few states — in the south and west, and in the
north‐east.(AP, Maharashtra , Karnataka, TN- >55%)
• Low prevalence states of Odisha, Kerala, Jharkhand,
Uttarakhand, Jammu & Kashmir, Arunachal Pradesh and
Meghalaya are showing rising trends in adult HIV
• Adult prevalence – 0.27% (2011)
• Men- 61% Women -39% Children –7%
• Urban > Rural
16. District-wise Scenario of AIDS
Category NACP-III Definition
A > 1% ANC prevalence in any of the sites in
the last 3 years
B < 1% ANC prevalence in all the sites during
last 3 years with > 5% prevalence in any
HRG site (STD/FSW/MSM/IDU)
C < 1% ANC prevalence in all sites during last
3 years with < 5% in all STD clinic
attendees or any HRG, with known hot
spots
D < 1% ANC prevalence in all sites during last
3 years with < 5% in all STD clinic
attendees or any HRG OR no or poor HIV
data with no known hot spots
Category NACP-III
A 156
B 39
C 296
D 118
New Districts 30
Total 609
17. Haryana : AIDS Scenario
• Total Estimated HIV Positive cases – 42000
• No. of AIDS cases (2012) - 2585
• Maximum no. of cases (Rohtak) - 590
• ART Centre - 1
• No. of persons registered(upto Feb’13) -11606
• Community care centre(CCC) - 1
• Drop in Centres - 2
18. www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
HIV Concentrated in HRG & Bridge Pop.
Source: HIV Sentinel Surveillance 2010-11 – A Technical Brief, NACO
19. HIV
TESTING
AND
COUNSELING
LINKAGE
TO CARE
ENROLLMENT
IN CARE
RETENTION
HIV
PREVENTION
GENERAL HIV
CARE
PREPARING
PEOPLE FOR
ART
MANAGING
COINFECTION
AND
MORBIDITIES
ART
INITIATION
(FIRST
LINE)
RETENTION AND
ADHERENCE
MONITORING ART
RESPONSE
MONITORING ARV
TOXICITY
SECOND
AND THIRD
LINE ART
Continuum of care
20. WHO HIV clinical stages
Short, flu-like
illness occurs 1-6
weeks after
infection
Infected person
can infect other
people
Average- 10 years
Mild symptoms
HIV in blood drops
to very low levels
Antibodies are
detectable in the
blood
The immune
system
deteriorates
Opportunistic
infections
(OI)start to
appear
Rapid decline in
the number of
CD4+ T cells
Opportunistic
infections become
severe and cancer
may develop
21. HIV Infection and Antibody Response
6 month ~ Years ~ Years ~ Years ~ Years
Virus
Antibody
Infection
Occurs
AIDS Symptoms
---Initial Stage---- ---------------Intermediate or Latent Stage-------------- ---Illness Stage---
Flu-like Symptoms
Or
No Symptoms
Symptom-free
<
----
----
22. HIV Testing and Counselling
VCTC
• Voluntary Counseling and Testing Centres
• People motivated were referred to these centres
VCCTC
• Voluntary Confidential Counseling and Testing Centres
• Emphasis on maintaining confidentiality
ICTC
• Integrated Counseling and Testing Centres
• Integration of VCCTC + PPTCT
PITC • Provider Initiated Counseling and Testing Centres
23. ICTC
ICTC
Stand-
Alone ICTC
Supported
financially and
logistically by
NACP
Facility
ICTC(F-ICTC)
Staff from existing
facilities trained in
counseling and
testing
PPP-ICTC
Established in
private facilities
based on F-ICTC
model
Mobile
ICTC
Takes the
package of
services to
community
12897
4508 8389
24. Topic Old Guidelines New Guidelines
HIV Testing
Initiating testing
and counseling
based on
referrals in
hospital set up
Community-based HIV
testing and counseling with
linkage to prevention, care
and treatment services is
recommended, in addition to
old guidelines.
Couples Voluntary HIV testing and counseling
HIV Testing & counselling
25. Working pattern of ICTC
HIV Suspect ICTC Counselor Reason for testing
Risk Assessment
Pre-test COUNSELING
consent
BLOOD TEST
HIV -ve
Post test COUNSELING
•Change risky life pattern
•Preventive measures
HIV +ve
confirmed
Post test COUNSELING
ART PPTCT Drop-in
Centres
27. COE
CENTRES OF EXCELLENCE
Provision of second line and
alternative first line ART
Training, research and mentoring
of ART centers linked to them
ART CENTRES
CD4 Testing
Pre ART care and counseling
ART provision
Treatment of OI
LINK ART CENTRES
Accessible and facilitate delivery of
ART
Monitoring patients on ART
COMMUNITY CARE CENTRES
Counseling for ARV treatment
preparedness and drug adherence,
nutrition and prevention
treatment of OI
referral and outreach services for
follow-up
Social support services
DROP IN CENTRES
Psychosocial support
Counseling
Sharing and caring
Referrals to ICTC, DOTS
Needle and syringe exchange
10
380
840
28. ART PLUS CENTRES
• Assessment and initiate
treatment for alternate
first line and second line
• Accessible and facilitate
delivery of second line
ART
• Viral load testing
• Number-21
LINK ART PLUS
CENTRES(LAC PLUS)
• ARV drug dispensing
• Enrolment of PLHIV in
HIV care and treatment
(Pre-ART Care)
• Monitoring of PLHIV on
ART
• Baseline lab tests
• Counseling on adherence,
nutrition & prevention
Delivery of HIV treatment and
care
30. HAART RegimensH
FIRST LINE
2NRTI+ 1NNRTI
PREFFERED REGIMEN
TDF + 3TC (or FTC) + EFV
SECOND LINE
2NRTI+ RITONAVIR
BOOSTED PI
PREFFERED REGIMEN
TDF + 3TC (or
FTC) + ATV/RTV
THIRD LINE
INTEGRASE
INHIBITOR+2ND
GENERATION
NNRTI+ PI
PREFFERED REGIMEN
RAL +ETV+RTV/DRV
31. Goals of ARV Therapy
• Reduce HIV-associated
morbidity and prolong
the duration and quality
of survival,
• Restore and preserve
immunologic function
• Maximally suppress
plasma HIV viral load
• Prevent HIV
transmission
32. Overview of WHO 2013
guidelines
• The 2013 consolidated guidelines compile new , existing
recommendations and other guidance across the continuum of
HIV care.
• Includes guidance on HIV diagnosis, general HIV care and the
strategic use of ARV drugs.
• Developed in accordance with procedures outlined by the
WHO Guidelines Review Committee and are based on the
GRADE (Grading of Recommendations, Assessment,
Development and Evaluation) system.
33. Recommendations: When to Start
TARGET
POPULATION
(ARV-NAIVE)
2010 ART GUIDELINES 2013 ART GUIDELINES
STRENGTH OF
RECOMMENDATION
& QUALITY OF
EVIDENCE
HIV+
ASYMPTOMATIC CD4 ≤350 cells/mm3
CD4 ≤500 cells/mm3 (CD4
≤ 350 cells/mm3
as a priority)
Strong, moderate-
quality evidence
HIV+
SYMPTOMATIC
WHO clinical stage 3 or 4
regardless of CD4 cell count
No change
Strong, moderate-
quality evidence
PREGNANT AND
BREASTFEEDING
WOMEN WITH HIV
CD4 ≤350 cells/mm3
or
WHO clinical stage 3 or 4
Regardless of CD4 cell
count or WHO clinical
stage
Strong, moderate-
quality evidence
HIV/TB CO-
INFECTION
Presence of active TB
disease, regardless of CD4
cell count
No change
Strong, low-quality
evidence
HIV/HBV CO-
INFECTION
Evidence of chronic active
HBV disease, regardless of
CD4 cell count
Evidence of severe chronic
HBV liver disease,
regardless of CD4 cell
count
Strong, low-quality
evidence
HIV+ PARTNERS IN
SD COUPLE
No recommendation
established
Regardless of CD4 cell
count or WHO clinical
stage
Strong, high-quality
evidence
34. Populations With No Specific
Recommendations
Insufficient evidence and/or favorable risk-benefit profile for ART
initiation at CD4 > 500 cells/mm3 (or regardless of CD4 count) in
the following situations:
Individuals with HIV who are 50 years of age and older
Individuals co-infected with HIV and HCV
Individuals with HIV-2
Key populations with a high risk of HIV transmission (e.g.:
MSM, sex workers, IDU)
These populations should follow the same principles and
recommendations as for other adults with HIV
35. Lab monitoring before starting ART
Phase of HIV
management
Recommended Desirable (if feasible)
HIV diagnosis
HIV serology,
CD4
TB screening
HBV (HBsAg) serology
Cryptococcus antigen if CD4 ≤100
Screening for STIs
Assessment for major NCD’s and
comorbidities
F/U before ART CD4 cell count (every 6–12 mths)
ART initiation CD4 cell count
Hemoglobin for AZT
Pregnancy test
Blood pressure
Urine dipsticks for glycosuria and
serum creatinine for TDF
LFT for NVP
36. Receiving ART CD4
(every 6 months)
HIV viral load
(at 6months after
initiating ART and
every 12 months )
Serum creatinine for TDF
Treatment
failure
CD4 (Persistent
CD4<100)
HIV viral load
(>1000)
Lab monitoring during ART
Phase of HIV
management
Recommended Desirable (if feasible)
40. HIV-TB Co-infection
• A setting with a high burden of TB and HIV refers to
settings with adult HIV prevalence ≥1% or HIV prevalence
among people with TB ≥5%
• Among PLHA, TB is the most frequent life-threatening
opportunistic infection and a leading cause of death(25%).
• HIV care settings should implement the WHO Three I’s
strategy:
– Intensified TB case-finding,
– Isoniazid preventive therapy (IPT)
– Infection control at all clinical encounters
41. DIAGNOSIS OF TB IN HIV
• Frequently negative sputum smears
• Atypical radiographic findings
• Resemblance to other opportunistic pulmonary infections like
pneumonia
WHY is it difficult to diagnose TB in HIV infected patient
Arrow points to
cavity in
patient's right
upper lobe
--typical finding
in patient with
TB
42. HIV infection increases the likelihood that new infection
with M. tuberculosis (due to immune suppression) will
progress rapidly to TB disease.
Among HIV-infected individuals, lifetime risk of developing
active TB is 50%, compared to 5-10% in persons who are not
HIV-infected.
In a person infected with HIV, the presence of other
infections, including TB, allows HIV to multiply more
quickly. This may result in more rapid progression of HIV
infection
HIV infected persons have approximately an 8‐times greater
risk of TB than persons without HIV infection
HIV-TB Co-infection
43. CD4 Cell count
ART Regimen ATT Regimen
CD4 < 50/ mm3 Start immediately Start immediately
CD4 < 250/ mm3 Start as soon as ATT
tolerated (2-4 wks)
Start immediately
CD4 250 -350/ mm3
Start after the initial
phase(8 wks) of TB
treatment
completed
Start immediately
CD4 >350/ mm3 Re-evaluate with repeat
CD4 count after TB
treatment
Start immediately
44. PPTCT :4 Pronged approach
Prevention of HIV in women
Prevention of unintended
pregnancies in HIV+ women
Prevention of HIV transmission
from HIV+ women to infants
Provision of care, treatment and
support to mothers living with HIV
and their families
45. PPTCT (Cont.)
• Without any intervention risk of transmission of HIV
from infected mother to her child is between 20-45%.
• SD-NVP is highly effective in reducing risk of
transmission from about 45% to less than 10%
• Multiple drugs for PPTCT can reduce transmission to less
than 5% if started early in pregnancy and continued
throughout period of delivery and breast feeding.
Adults
57 %
Children
35%
46. PMTCT
program option
Pregnant and breastfeeding
women with HIV
HIV-exposed infant
Use lifelong ART
for all pregnant
and breastfeeding
women
(“Option B+”)
Regardless of WHO clinical
stage or CD4
Breastfeeding
Replacement
feeding
Initiate ART and maintain
after delivery & cessation
of breastfeeding
6 weeks of
infant
prophylaxis
with
once-daily NVP
6 weeks of infant
prophylaxis with
once-daily NVP
Use lifelong ART
only for pregnant
and breastfeeding
women eligible
for treatment
(“Option B”)
Eligible for
Treatment
(CD4 Count)
Not eligible
for
treatment
Initiate ART
and maintain
after delivery
and cessation
of
breastfeeding
Initiate ART
and stop after
delivery
and cessation
of
Breastfeeding
47. Establish HIV Status of Pregnant Women
HIV -venewly detected HIV infection
Continue ART
From ICTC collect the blood
Sample for CD4 and sent it to
ART center and refer women to
there
ART Center: Initiate ART to HIV +ve pregnant mother regardless of
WHO Clinical Stage and CD4counts
Preferred Regimen : TDF+3TC+EFV
ART center will collect sample for baseline and other investigations
Repeat HIV as
per guidelines for
window period
&h/o risk factor
Known HIV infected case
and already receiving ART
48. Mother :Continue ART during
labour and
delivery(intrapartum)
Mother: Continue ART(Postpartum)
Infant: Daily NVP from birth until 6 weeks of
age then stop
(Irrespective of choice of infant feeding)
Exclusive BF/RF
Continue ART
Continued
49. Duration of BF in HIV
• Breastfeeding should only stop once a nutritionally
adequate and safe diet without breast-milk can be
provided.(AFASS Criteria)
– Acceptable
– Feasible
– Affordable
– Sustainable
– Safe
50. HIV in Body Fluids
Semen
11,000 Vaginal
Fluid
7,000
Blood
18,000
Amniotic
Fluid
4,000 Saliva
1
50
Semen
11,000
Vaginal
Fluid
7,000
Amniotic
Fluid
4,000
Saliva
1
Average number of HIV particles in 1 ml of these body fluids
53. HIV: Prophylaxis
• Standard Precautions:
Hand washing
Use of protective barriers e.g- gloves,masks,goggles,gowns
Safe handling and safe disposal of sharps
Respiratory hygiene and cough etiquettes
Safe decontamination and disposal of contaminated waste
54. Post-exposure Prophylaxis
Comprehensive management given to minimize the risk of infection
following potential exposure to blood-borne pathogens e.g. HIV.
This includes:
1. First aid
2. Counseling
3. Risk assessment
4. Relevant laboratory investigations based on informed
consent of the exposed person.
5. Depending on the risk assessment, the provision of short
term (4 weeks) of ART.
6. Follow up and support
55. • Post-exposure prophylaxis (PEP) has its greatest effect if begun
within 2 hours of exposure. There is little benefit if started >72
hours.
• The prophylaxis needs to be continued for 4 weeks (28 days).
Preferred PEP regimen :
• Initially:
– 2 drug regimen (Zidovudine + Lamivudine)
– then 3 drug regimen : after expert opinion ( AZT + 3TC +
NVP)
• Clinical follow-up: the exposed person must be monitored for the
eventual appearance of signs indicating an HIV. These symptoms
almost always appears within 3 to 6 weeks after exposure.
• Laboratory follow-up : after exposure testing at 3 months
and 6 months is recommended.
Post-exposure Prophylaxis
56. Oral pre-exposure prophylaxis
Serodiscordant couples daily oral PrEP ( TDF or TDF + FTC)
Men and transgender
women
daily oral PrEP (Specifically TDF +
Emtricitabine)
ART for prevention
among serodiscordant
couples
PLHIV in serodiscordant couples who
start ART for their own health, ART is also
recommended to reduce HIV transmission
to the uninfected partner.
HIV-positive partners with a CD4 count
≥350 cells/mm3.
HIV prevention based on ARV
drugs
57. Post-exposure prophylaxis for occupational
and non-occupational exposure to HIV
Post-exposure
prophylaxis
for women
within
72 hours of
a sexual assault
• Recommended duration of PoEP is
28 days,
• First dose as soon as possible
within 72 hours
• The choice based on first-line ART
regimen.
58. HIV Vaccine
Need
Despite the remarkable achievements in development of anti-retroviral
therapies and recent advances in new prevention technologies, the rate of new
HIV infections continues to outpace efforts on prevention and control.
Challenges
• H.I.V. mutates rapidly; H.I.V. mutates in one day as much as influenza
viruses do in a year.
• The virus has developed multiple mechanisms to evade the body’s defenses
• Targets the very cells (CD4) that coordinate the immune response to viral
infections.
• Broadly neutralising antibodies usually appear between 2-- 4 years but by
that time the antibodies cannot save them because they are overwhelmed by
the mutating virus.
59. HIV Vaccine:the new hope
• AIDSVax
Recombinant protein (HIV gp120)
adjuvant with alum
Recombinant adeno associated
virus vaccine(rAAV)
Recombinant adenovirus type-5 vaccine
containing HIV gag, pol and nef genes
RV144
Canarypox vector prime + monomeric
gp120 boost
Failed in Phase II
trials
Failed in MSM
Paradoxically increased
the risk of infection
among uncircumcised
men with exposure to
the virus used in the
vaccine.
vaccine with the
greatest promise till
date.
31% efficacy in Phase
III trials
60. NACP – IV: Priorities
Preventing new infections
Preventing of Parent to child transmission
Focusing on IEC strategies for behaviour change in
HRG, awareness among general population and
demand generation for HIV services
Providing comprehensive care, support and treatment to
eligible PLHIV
Integrating HIV services with health systems in a
phased manner
Reducing stigma and discrimination through greater
involvement of people living with HIV(GIPA)
61. •Needle-Syringe Exchange Programme and Opioid
Substitution Therapy for IDUs
•Targeted Interventions for High Risk Groups (FSW,
MSM, IDU, Truckers & Migrants)
• Link Worker Scheme for rural population
•Prevention & Control of Sexually Transmitted Infections
•IEC, Social Mobilization & Mainstreaming
•Condom promotion
•Blood safety
•Counselling & Testing Services (ICTC, PPTCT, HIV/TB)
•First line & second line
ART
• Care &Support Centres
•HIV-TB Coordination
•Focus on PPTCT
•Treatment of
Opportunistic Infections
Prevention is the main stay
High risk
populations
Low risk
populations
People living with
HIV/AIDS
Care, Support and Treatment
NACP IV Strategies
Capacity BuildingStrategic Information Management
62. References
• Joint United Nations Programme on HIV/AIDS (UNAIDS). Report
on the global AIDS epidemic .UNAIDS 2013
• National AIDS Control Organisation. About NACO;NACO 2013.
Available from: http://www.nacoonline.org/About_NACO/ .
• Chawla S, Sahoo SS, Jain RB, Khanna P, Mehta B, Singh I.HIV-Is a
vaccine the answer? Hum Vaccin Immunother 2013;10(1).
• www.ncbi.nlm.nih.gov/pubmed/15817963
• medind.nic.in/nac/t03/i3/nact03i3p11.pdf
• World Health Organization. Global HIV/AIDS Response– Epidemic
update and health sector progress towards Universal Access –
Progress Report 2013.
63. References
• WHO. Antiretroviral Therapy for HIV infection in Adults and
Adolescents in Resource-limited settings: Towards Universal
Access. Recommendations for a public health approach. 2006
revision.
• medind.nic.in/nac/t03/i3/nact03i3p11.pdf
• Guidelines for the Use of Antiretroviral Agents in HIV
Infected Adults and Adolescents,2013.Available from:
(http://aidsinfo.nih.gov/guidelines)
• International AIDS committee(IAS);Kualalumpur,Malaysia,30
June – 3July 2013
Notas do Editor
François-Xavier Bagnoud Center, UMDNJ
INITIATE ART REGARDLESS OF CD4 COUNT OR CLINICAL STAGE
RECOMMENDATION
ADULTS WITH HIV…
…and active TB disease
Strong, low-quality evidence
…and HBV co-infection with severe liver disease
Strong, low-quality evidence
…who are pregnant or breastfeeding
Strong, moderate-quality of evidence
…in a HIV serodiscordant partnership
Strong, high-quality evidence
CHILDREN < 5 YEARS OLD WITH HIV
Infants diagnosed in the first year of life
Strong, moderate-quality of evidence
Children infected with HIV between one and below five years of age
Conditional, very-low-quality evidence
ICTC: Integrated Counseling and Testing Centres about 5000 in numbers
PPTCT: Prevention of Parent to Child Transmission Centres for antenatal mothers
Opportunistic infections are mainly tuberculosis, chronic diarrhoea, skin infections, pneumonias, fungal and viral infections like herpes etc