HIV and Skin

• HIV-1 and HIV-2 are types of HIV.
• Both types are transmitted the same way.
• Both are associated with similar opportunistic infections and AIDS.
• HIV-1 is more common worldwide.
• HIV-2 is found predominantly in West Africa, Angola, and Mozambique.

Differences between HIV-1 and HIV-2

• HIV-2 is less easily transmitted than is HIV-1.
• HIV-2 is less pathogenic, meaning that the period between initial infection and illness is longer.
• While HIV-2 can be transmitted from an infected mother to her child, this appears to be rare (0% to 5% transmission rate in breastfed infants in the absence of any interventions).

Global Estimates for Adults and Children

• People living with HIV: 39.5 million (34.1–47.1 million)
• New HIV infections in 2006: 4.3 million (3.6–6.6 million)
• Deaths due to AIDS in 2006: 2.9 million (2.5–3.5 million)

Composition

• 3 viral enzymes
• 1. Reverse transcriptase - Converts viral RNA into DNA.
• 2. Integrase - Incorporates viral DNA into host cell chromosomes (provirus).
• 3. Protease - Cleaves precursor protein GP160 into GP 120 and GP 41 so that new viruses can be assembled.

• 3 genes
• 1. Gag - gp 55 - p24 and p18
• 2. Pol – Reverse transcriptase and integrase
• 3. Env - 160 - gp120 and 14

How is HIV transmitted?

• Sex
• Heterosexual (M to F, F to M)
• Homosexual (male to male, female to female)
• Bisexual
• Parenteral
• Mother to child.
• "Unknown"

Sexual contact

• Unprotected sexual intercourse (vaginal, oral, or anal)
• Heterosexual transmission is the primary mode of acquiring HIV in developing countries.
• Direct contact with HIV-infected body fluids such as semen and cervical and vaginal secretions
• Women, especially young girls, are more likely than men to become infected following heterosexual intercourse due to biological, socio-economic and cultural reasons.
• Cases of HIV infection resulting from sexual abuse of children, and even infants, have been reported.
• Role of STIs

Estimates of HIV transmission risk per contact

Sex Act	Estimated Risk of Acquiring HIV Infection Per Contact (%)
Female to male vaginal sex	0.0003-0.0014%
Male to female vaginal sex	2.3-20 x above
Receptive anal sex	0.82
Insertive anal sex	0.06
Receptive fellatio	0.04

Parenteral

• Injection drug use
• Injection of drugs with needles or syringes contaminated with HIV
• Blood-to-blood transmission
• Transfusion with HIV-infected blood/blood products
• Direct contact with HIV-infected blood
• Needlestick injuries
• Traditional Practices
• Group circumcision
• Tattoos/scarification
• Barbing
• Nail cutting
• Cupping, etc.

Not aware of studies that confirmed these.

Mother to Child Transmission (MTCT)

From mothers who are HIV-positive to their infants:

• Pregnancy
• Labor, delivery
• Breastfeeding

• Major target cells: CD4 T-lymphocytes and macrophages
• Binding of the viral envelope glycoprotein gp120 to the receptor as well as CCR5 or CXCR4 (Coreceptors) on the host cell CD4
• Fusion of the viral envelope with the cell membrane mediated by gp41, which undergoes conformational change.
• Viral core and its components are released into the cytoplasm
• Reverse transcriptase converts the single-strand viral RNA into a DNA duplex
• Integrase inserts (integrates) the DNA duplex into the host cell genome
• Once integrated into the host cell genome, the virus DNA is copied by the host cell for translation into HIV regulatory proteins
• Finally, HIV core containing HIV RNA, core proteins & enzymes is assembled using protease enzyme.
• Assembly moves to the cell surface and acquires envelope proteins by budding through the cell membrane
• HIV not only infects the CD4 cells, but also establishes infection in the CNS, lymphoid tissue, and testes (virus reservoirs)
• HIV reverse transcriptase is very error-prone, and therefore, introduces a high mutation rate in the viral genome

Characteristic viral load and CD4 changes over time in HIV/AIDS

Seroconversion

• Develop antibodies 4 to 6 weeks after infection
• May take as long as 3 months for antibodies to develop.
• The period of time between when a person is infected with HIV and when the antibody test result is positive is called the "window period."

CDC 1993 Revised Classification System for HIV Infection and Expanded AIDS Surveillance Case Definition for Adolescents and Adults
	Clinical Categories
CD4+ T Cell Categories	A Asymptomatic, Acute (Primary) HIV or PGL	B Symptomatic, Not A or C Conditions	C AIDS Indicator Conditions
>500/mL	A1	B1	C1
200-499/mL	A2	B2	C2
< 200/mL	A3	B3	C3

Persons in category A3, B3, C1, C2, and C3 have AIDS under the CDC 1993 revised classification system for HIV infection and expanded AIDS surveillance case definition for adolescents and adults.

AIDS-indicator conditions

Fungal Infections:

• Candidiasis of bronchi, trachea, and lungs
• Candidiasis, oesophageal
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Histoplasmosis, disseminated or extrapulmonary

Parasitic Infections:

• Cryptosporidiosis, chronic intestinal (>1 month duration)
• Isosporiasis, chronic intestinal (>1 month)
• Toxoplasmosis of brain

Viral Infections:

• Cytomegalovirus disease (other than liver, spleen, or nodes)
• Herpes simplex: chronic ulcer(s) (>1-month duration) or bronchitis, pneumonitis, or oesophagitis
• Kaposi’s sarcoma
• Progressive multifocal leucoencephalopathy

Bacterial Infections:

• Salmonella septicaemia, recurrent

Hematological Conditions:

• Lymphoma, Burkitt’s (or equivalent term)
• Lymphoma, immunoblastic (or equivalent term)
• Lymphoma, primary in brain

Pulmonary Infections:

• Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
• Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
• Pneumocystis jiroveci pneumonia
• Pneumonia, recurrent

Other Conditions:

• Encephalopathy, HIV-related
• Wasting syndrome, HIV-related
• Cervical cancer, invasive

Clinical Features of HIV Infection:

• Acute HIV infection
• Primary generalized lymphadenopathy (PGL)
• Paediatric AIDS
• Central nervous system (CNS) AIDS (AIDS dementia complex)
• Full-blown AIDS
• “African presentation”

Differences in Clinical Presentation:

1. In the United States, homosexuals form the majority of patients, resulting in about a 9:1 male-to-female ratio. In Africa, the male-to-female ratio is 1:1, consistent with heterosexual transmission.
2. Typical adult AIDS patients in the United States present with symptoms such as fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and, in many cases, secondary neoplasms.
3. In African AIDS, patients often present with different symptoms, including asthenia (the most common), persistent diarrhea and fever lasting more than one month, sometimes accompanied by night sweats. These symptoms may appear together or in isolation. Some patients also develop oral candidiasis and other opportunistic infections, with the most common being cryptococcal meningitis.
4. In America and Europe, pneumocystis jiroveci pneumonia is the most common opportunistic infection in AIDS patients. Opportunistic infections account for approximately 80% of deaths in AIDS patients.

Phases of HIV Infection:

1. The Early, Acute Phase:
   • Represents the initial response of an immunocompetent adult to HIV infection.
   • Characterized by a high level of virus production, viremia, and widespread seeding of the lymphoid tissues.
   • Approximately 100 billion new viral particles are produced every day, and 1-2 billion CD4+ T-cells die each day.
   Symptoms of Acute Phase:
   • Fever
   • Adenopathy
   • Pharyngitis (non-exudative)
   • Rash (morbilliform, maculopapular)
   • Diarrhea
   • Headache
   • Nausea/vomiting
   • Neurologic (Guillain–Barre Syndrome, encephalitis, aseptic meningitis)
2. The Middle, Chronic Phase:
   • Represents a stage of relative containment of the virus.
   • Associated with a period of clinical latency.
   • Virus replication continues for several years, predominantly in the lymphoid tissues, in the setting of a largely intact immune system.
   • Patients are either asymptomatic or develop persistent generalized lymphadenopathy (PGL). Many patients have herpes zoster, oral thrush, or thrombocytopenia.
3. The Final, Crisis Phase:
   • Characterized by a breakdown of host defense, a sudden and rapid viremia, and clinical disease.
   • Typically, the patient presents with marked weight loss, chronic diarrhea, and fever lasting more than 1 month.
   • CD4 cells are generally below 200 cells/µl, and opportunistic infections (OIs) supervene in this stage.
   • The patient is said to have developed AIDS. The clinical picture will then depend on the type of OI or cancer.

• Isolation of the virus
• Detection of viral antigen
• Detection of viral antibody

Detection of viral antigen and isolation of the virus are quite expensive and technically demanding. They are therefore not widely used.

Diagnosis of AIDS:

AIDS can be diagnosed using the WHO Clinical Case Definition in adults where diagnostic facilities are limited:

AIDS is defined by the existence of:

• AT LEAST 2 major signs associated with
• AT LEAST 1 minor sign in the absence of known causes of immunosuppression.

MAJOR SIGNS:

• Weight loss >10% body weight
• Chronic diarrhoea (lasting >1 month)
• Fever intermittent or constant (lasting >1 month)

MINOR SIGNS:

• Persistent cough (>1 month)
• Generalized pruritic dermatitis
• Recurrent herpes zoster
• Oropharyngeal candidiasis
• Chronic progressive and disseminated herpes virus infection
• Generalized lymphadenopathy

Initial Investigations should include:

• Complete blood count (haemoglobin [Hb], haematocrit [Hct], white blood count [WBC] with differentials, platelets, MCV).
• Liver function tests (alkaline phosphatase, alanine transferase [ALT], aspartate transaminase [AST], gamma glutamyl transpeptidase [GGT], lactate dehydrogenase [LDH], protein/albumin.
• Other routine baseline investigations not related to HIV (e.g., fasting blood glucose, cholesterol [total], triglycerides, high-density lipoprotein, low-density lipoprotein, blood urea nitrogen [BUN], and creatinine).
• HBsAg
• anti-HBs
• anti-HCV
• VDRL (and confirmatory test, as it may be difficult to diagnose syphilis in HIV-positive patients).
• Toxoplasmosis, cytomegalovirus, cryptococcal antigen, Epstein-Barr virus - not useful as routine screening tests.
• Pulmonary function tests and chest radiography as a baseline may be helpful.
• Tuberculin skin test. If negative, repeat in two weeks and do anergy screen if CD4 count is less than 200/mm3.
• CD4 counts
• Pap smear and swabs for culture and sensitivity and yeast in women.
• Viral load

NB. Other relevant investigations may be indicated depending on the presenting features and possible aetiology.

Treatment Goals:

Clinical:

• Prolong survival
• Prevent disease progression
• Minimize toxicity

Virological:

• Maximal and durable suppression of viral load for as long as possible to below detectable levels (currently defined as <50 copies/ml)

Immunological:

• Preserve immune function (CD4 cell count in normal range)

Public health:

• Reduce HIV transmission
• Preserve future treatment options

Management:

Caring for people with HIV infection is extremely difficult for a number of reasons:

1. HIV infection is incurable.
2. Infected individuals need to be counseled to ensure they do not transmit the disease to others.
3. Diagnosing HIV-related diseases may be problematic, as they often present with atypical clinical manifestations and may occur simultaneously, even in the same organs.
4. Unavailability of treatment for some HIV-related diseases.
5. Patients often develop serious adverse effects to drugs.
6. The number of healthcare workers with experience in counseling and managing people with HIV is limited, particularly in Africa.

CRITICAL QUESTIONS IN HAART:

• When to initiate therapy?
• What is the optimal initial therapy?
• When to change therapy?
• What are the optimal subsequent therapies?

WHEN TO INITIATE HAART?

The initiation of Highly Active Antiretroviral Therapy (HAART) depends on several factors:

1. The presence of an AIDS-defining illness irrespective of HIV RNA level or CD4+ cell count.
2. All patients with CD4+ cell count <200/mL irrespective of HIV RNA level.
3. All patients with CD4+ cell count between 200-350/mL (especially if HIV RNA level >20,000 copies/mL).
4. Most patients with CD4+ cell count >350/mL only if HIV RNA level >55,000 copies/mL.

WHO recommends that in ARV treatment programs in resource-limited settings HIV-infected adolescents and adults should start ARV therapy when they have:

• WHO stage IV of HIV disease (clinical AIDS), regardless of CD4 count.
• WHO stages I, II, or III of HIV disease, with a CD4 count below 200/mm3.
• WHO stages II or III of HIV disease with TLC below 1200/mm3.

Special Considerations for ARVs:

1. Pregnancy: Efavirenz is contraindicated in pregnancy because it has been found to be teratogenic in animals and associated with myelomeningoceles in humans.
2. HIV-associated tuberculosis: Because of the interactions between NNRTIs, particularly nevirapine, PIs and rifampin.

Risks and Benefits of Early Therapy:

When considering early therapy for HIV, it's essential to weigh the potential risks and benefits:

Benefits of early therapy:

• Control of viral replication is easier.
• Prevention of immune system compromise.
• Lower risk of resistance with complete viral suppression.
• Possible decreased risk of HIV transmission.

Risks of early therapy:

• Drug-related reduction in quality of life.
• Greater cumulative drug-related adverse events.
• Earlier development of drug resistance.
• Limitation of future antiretroviral Rx options.

Special Considerations for ARVs:

1. Pregnancy: Efavirenz is contraindicated in pregnancy because it has been found to be teratogenic in animals and associated with myelomeningoceles in humans.
2. HIV-associated tuberculosis: Because of the interactions between NNRTIs, particularly nevirapine, PIs and rifampin.

Risks and Benefits of Early Therapy:

When considering early therapy for HIV, it's essential to weigh the potential risks and benefits:

Benefits of early therapy:

• Control of viral replication is easier.
• Prevention of immune system compromise.
• Lower risk of resistance with complete viral suppression.
• Possible decreased risk of HIV transmission.

Risks of early therapy:

• Drug-related reduction in quality of life.
• Greater cumulative drug-related adverse events.
• Earlier development of drug resistance.
• Limitation of future antiretroviral Rx options.

Monitoring of HAART:

When on Highly Active Antiretroviral Therapy (HAART), monitoring involves the following:

• Measure plasma HIV RNA levels at various intervals:
• Immediately prior to initiation of Rx
• At 2-8 weeks after Rx
• 3-4 months after the start of therapy
• Repeat every 3-4 months while being on therapy
• In case of a clinical event or a significant decline in CD4+ T cells
• CD4+ T cell counts at the time of diagnosis and generally every 3-6 months thereafter

Changing Regimens/Switching Drugs:

During the course of therapy, there are several reasons to consider changing regimens:

1. Toxicity:
• Adverse reactions to a particular ARV drug in the regimen.
• Change only the offending drug, retaining accompanying ARV drugs.
2. Inconvenience of regimen
3. Pregnancy
4. TB treatment
5. Therapy Failure:
• Inability of the drug regimen to suppress the replication of the HIV virus.
• Change the entire regimen.

Definition of Therapy Failure:

Therapy failure in the context of HIV treatment can be defined based on clinical, immunological, and virological criteria:

Clinical:

• Onset of new or recurrence of opportunistic infections
• Onset or recurrence of WHO stage III-defining condition

Note: Consider Immune Reconstitution Inflammatory Syndrome (IRIS).

Immunological:

• Return of CD4 count to pretherapy level
• 30% fall in CD4 count from peak level during therapy
• Failure to achieve a CD4 cell count increase of 50-100 cells per year

Virological:

• Viral load not suppressed to undetectable levels after 4-6 months of ART
• A persistent increase in viral load following a period of adequate suppression

CROSS-RESISTANCE- Considerations for Changing Antiretroviral Regimens:

• Avoid changing among NNRTIs because viral strains that become resistant to one NNRTI have reduced susceptibility to other NNRTIs.
• Cross-resistance is also seen among PIs, such as Ritonavir and Indinavir.
• In general, cross-resistance is not a major concern with NRTIs (Nucleoside Reverse Transcriptase Inhibitors).
• Use of drug resistance testing in this setting is helpful.

The absence of a curative treatment or vaccine makes prevention of HIV transmission essential to controlling the epidemic.

• General public education about HIV to prevent its spread.
• Patients at risk should be targeted for specific education and risk reduction. Different outlets for information dissemination such as clinics, radio, television, traditional institutions, and public fora should be used.
• Active collaboration between organs of society including the healthcare sector, political class, general population, and faith-based organizations.
• Within the healthcare sector, clinicians require ongoing collaboration with social workers, health education specialists, mental health specialists, and patients.
• In all settings, especially those that are resource-poor, selection of the most cost-effective interventions is imperative because allocation of resources to one intervention may prevent implementation of other interventions.
• Address squarely the issue of sexual promiscuity or excessive sexual activity.
• Restrict themselves to one partner only, if married.
• If unmarried, they should abstain or restrict themselves to the person they know best.
• At worst, condom use should be emphasized to those who cannot abstain.
• People must not shy away from screening themselves periodically if they expose themselves to more than one partner.
• Provide early diagnosis and treatment of STIs.
• Make HIV testing and counseling widely available.
• Provide suitable counseling for women who are HIV-negative.
• Prevention of unintended pregnancies among HIV-positive women.
• Testing and counseling of pregnant women.
• ARV Prophylaxis for mother-child pairs.
• Modification of infant feeding practices and support.
• Safe blood transfusion practices (transfuse only HIV-negative blood).
• Use sterile materials like needles, blades, and instruments.